Cancer-Fighting Agents

Simple Summary: This ginger compound pushes cancer cells into overwhelming stress: it floods them with ROS, jams their protein-folding machinery, and flips on death switches—while turning down pathways they use to invade and spread. It also hits stem-like tumor cells that seed relapse. Evidence is mostly lab/animal so far, but it’s a strong adjunct candidate in preclinical work.

Mechanisms: 6-Shogaol, the dehydrated form of 6-gingerol, kills cancer cells by triggering mitochondrial/ER-stress apoptosis driven by reactive oxygen species (ROS) and the PERK–eIF2α–ATF4–CHOP axis (up to DR5 activation). It suppresses NF-κB/IKK and STAT3 signaling, lowering MMP-2/MMP-9 and EMT drivers (Snail/Slug/vimentin), which reduces invasion and metastasis. It also targets cancer stem-like cells (e.g., CD44+CD24−/low/ALDH1+ spheres) and can induce paraptosis-like vacuolization. In models, 6-shogaol enhances sensitivity of drug-resistant cells (e.g., gefitinib-resistant ovarian) via ER-stress–mediated apoptosis.

Note: Human evidence: Very limited; no clinical trials proving anti-cancer benefits in humans. Ginger extracts (containing 6-shogaol) have been studied for nausea in cancer patients, but not for tumor effects. Safety: Generally safe in food/tea amounts (e.g., from fresh ginger). High doses or extracts may cause GI upset (heartburn, diarrhea), mouth irritation, or bleeding risk (due to anti-platelet effects—avoid with anticoagulants like warfarin). Not recommended in pregnancy or with gallstones. Bioavailability is low; nanotechnology may improve in future. Adjunct role: Potential to enhance chemo (e.g., in resistant cells), but discuss with oncologist to avoid interactions. Do not self-administer high doses without supervision.

Simple Summary: Acemannan is a compound found in aloe vera that boosts your immune system’s cancer-fighting activity. It helps the body recognize tumors and slows their growth. One human study even showed better outcomes when acemannan was used with chemo.

Mechanisms: Acemannan stimulates macrophages, dendritic cells, and T-cells to release IL-1, IL-6, TNF-α, and IFN-γ, enhancing the immune system’s ability to recognize and attack tumors. It also promotes antigen presentation and slows tumor proliferation, migration, and stemness in vitro. In combination with chemotherapy, it may enhance tumor regression and improve survival.

Note: All but one of these studies were performed in mice or canines. The human trial (PMID 19368145) was larger and concluded: “The percentage of both objective tumor regressions and disease control was significantly higher in patients concomitantly treated with Aloe than with chemotherapy alone, as well as the percent of 3-year survival patients.” In that trial, patients received 10 ml of aloe extract three times daily alongside chemotherapy.

Simple Summary: AHCC, a shiitake mushroom extract, supercharges your immune system's NK and T-cells to better spot and destroy cancer cells. It also nudges tumors toward self-destruction and teams up with chemo to make it more effective while easing side effects like nausea or low blood counts. Human studies show promise for liver, pancreatic, and ovarian cancers, especially as an add-on to standard treatments.

Mechanisms: AHCC is a proprietary alpha-glucan-rich extract from cultured shiitake (Lentinula edodes) mycelia, with low-molecular-weight polysaccharides (primarily alpha-1,4-glucans with alpha-1,3 branches, ~5 kDa). It modulates immunity by priming Toll-like receptors (TLR2/TLR4) on intestinal epithelium and immune cells, enhancing dendritic cell maturation, NK cell cytotoxicity, and T-cell (CD4+/CD8+) proliferation. This leads to upregulated cytokine production (IL-12, IFN-γ, TNF-α) and nitric oxide regulation. Anticancer effects include induction of tumor cell apoptosis (Bax↑/Bcl-2↓, caspase-3/7 activation), overcoming multidrug resistance via downregulation of Heat Shock Factor 1 (HSF1) and HSP27, and synergy with chemotherapy (e.g., gemcitabine, 5-FU) by improving drug efficacy and reducing toxicities. It also exhibits anti-inflammatory and antioxidant properties, protecting against oxidative stress and chemo-induced adverse events. Pharmacokinetically, AHCC is well-absorbed orally with good bioavailability, peaking in 1-2h and exerting systemic immune effects.

Note: Ideal as an immune-boosting adjunct during chemo; take on empty stomach for best absorption. Monitor for CYP2D6 induction with certain drugs. Not a standalone cure—pair with conventional care under provider guidance. Limited long-term oncology data; ongoing trials may clarify broader use.

Simple Summary: This medicinal mushroom helps wake up your immune system. It supercharges the cells that fight cancer—especially NK cells—and can help shrink tumors in early studies. Some clinical trials have shown improvements in immune markers for cancer patients who take it.

Mechanisms: Agaricus blazei is rich in β-glucans that activate Dectin-1 and TLR-2 receptors on immune cells, leading to the production of IL-12 and IFN-γ. This stimulates natural killer (NK) cells, macrophages, and cytotoxic T-cells. In vitro and in vivo studies show it inhibits tumor growth, induces apoptosis, and may reverse immunosuppression in cancer patients.

Note: Human evidence includes small trials showing immune marker improvements (e.g., NK activity ↑) and QoL benefits in cancer patients, but no large RCTs for tumor outcomes. Preclinical data strong for antitumor effects. Safety good up to 5.4 g/day in phase I trials; monitor for GI effects.

Simple Summary: This standardized garlic extract pushes cancer cells toward programmed death, starves tumors by cutting off new blood vessels, and supports immune attack (NK cells). A small clinical trial suggests it can slow growth of colon polyps, but direct tumor-shrinkage evidence in people is still limited.

Mechanisms: AGE is enriched in stable, water-soluble organosulfurs—especially S-allylcysteine (SAC) and S-allyl-mercaptocysteine (SAMC)—that trigger mitochondrial apoptosis (Δψm loss, Bax↑/Bcl-2↓ → caspase-9/-3 activation), arrest the cell cycle, and suppress pro-tumor pathways (NF-κB, COX-2). It inhibits angiogenesis (↓VEGF/VEGFR2; impaired endothelial migration/tube formation) and reduces invasion in colorectal and other models. In humans, AGE increased natural-killer (NK) cell number/activity in advanced digestive-cancer patients and, in a randomized trial, slowed the growth/number of colorectal adenomas (precancerous lesions).

Note: Why AGE > raw garlic for cancer: AGE provides consistent, standardized SAC (stable, bioavailable, low-toxicity) with human data for adenoma suppression and immune activation. Raw garlic’s key compound allicin is highly unstable and varies with crushing/cooking, making dose and effects unpredictable.

Simple Summary: Albendazole is a common deworming drug now studied for cancer because it interferes with tumor cell division. Lab tests show it shrinks tumors in models of colon, liver, and skin cancers, and a small human trial noted some benefits but warned of blood cell risks.

Mechanisms: Albendazole binds to β-tubulin, disrupting microtubule formation and causing mitotic arrest, which leads to apoptosis and inhibition of glucose uptake in cancer cells. It suppresses NF-κB signaling to reduce inflammation and angiogenesis, and promotes ubiquitin-mediated PD-L1 degradation to enhance immunotherapy. Preclinical models demonstrate anti-proliferative effects in liver, colon, pancreatic, melanoma, and other cancers; human data show potential but highlight hematologic toxicity.

Note: Strong preclinical evidence across multiple cancer types; human data limited to small pilot studies (e.g., PMID 11474247: 7 patients with advanced HCC/CRC, some tumor marker stabilization but 3/10 developed severe neutropenia, 1 possibly treatment-related death). Promising for repurposing but requires careful monitoring for myelosuppression.

Simple Summary: ALA recharges the body’s own antioxidants and turns down cancer growth switches (AKT, NF-κB, HIF-1α). That can reduce blood-vessel growth and glycolysis and help tumor cells self-destruct. Human studies mostly show symptom/metabolic benefits; direct tumor-control evidence is still early.

Mechanisms: Alpha-lipoic acid (ALA) is a mitochondrial coenzyme and redox regulator that restores glutathione, vitamin C, and vitamin E. It inhibits tumor-promoting pathways such as AKT, NF-κB, and HIF-1α, suppressing angiogenesis and glycolysis in cancer cells. ALA has been shown to induce apoptosis, arrest the cell cycle, and reduce oxidative stress in various cancer types including ovarian, lung, and breast cancer models.

Simple Summary: Andrographolide turns down master survival switches (NF-κB, STAT3) and hypoxia signaling (HIF-1α/VEGF), pushes cancer cells toward apoptosis, slows the cell cycle, and often blocks PI3K/Akt/mTOR. It also cuts invasion programs like MMP-2/9 and CXCR4. Because oral levels are low and short-lived in people, it’s best viewed as a chemo-sensitizer/adjunct rather than a stand-alone anticancer drug right now.

Mechanisms: Andrographolide is a diterpenoid lactone that acts as a Michael acceptor. It directly and covalently modifies NF-κB p50 at Cys62 to block NF-κB DNA binding, suppressing transcription of survival, inflammatory, and pro-metastatic genes (e.g., COX-2, MMP-9). It inhibits JAK/STAT3 signaling (sensitizing cells to doxorubicin and other cytotoxics), downregulates HIF-1α (via PI3K/Akt suppression and ubiquitin-mediated degradation) and thereby lowers VEGF and angiogenesis. Across tumor models it induces mitochondrial apoptosis (caspase-3/7 activation, PARP cleavage, Bax↑/Bcl-2↓), triggers G0/G1 or G2/M arrest, and modulates autophagy in a context-dependent way (most often via PI3K/Akt/mTOR inhibition). It also reduces migration/invasion by lowering MMP-2/9, CXCR4, HER2 and related programs. PK in humans shows low oral bioavailability and short half-life; most clinical data are non-oncology, so anticancer efficacy in humans remains unproven.

Note: Consider for protocols aiming to suppress NF-κB/STAT3/HIF-1α and PI3K/Akt/mTOR, reduce angiogenesis/invasion, and sensitize to chemo or ROS hits. Watch for context-dependent autophagy effects (can inhibit or, with some analogs/conditions, induce it). Human cancer outcome trials are lacking; oral bioavailability is limited—formulation and timing matter.

Simple Summary: Apigenin slows cancer-cell division, pushes them toward self-destruction, and reduces blood-vessel growth. It dials down PI3K/AKT and NF-κB and can raise ROS inside tumor cells. Most evidence is lab/animal; concentrated extracts are needed for pharmacologic effects beyond diet.

Mechanisms: Apigenin is a flavonoid that exerts anticancer effects by inducing G2/M cell cycle arrest, inhibiting angiogenesis (via VEGF downregulation), and acting as a topoisomerase-II poison. It modulates key signaling pathways such as PI3K/AKT, MAPK, and NF-κB, inhibits cancer cell migration and invasion, promotes apoptosis through mitochondrial disruption, and increases intracellular ROS generation selectively in cancer cells.

Note: Best for protocols targeting PI3K/NF-κB suppression, angiogenesis, or ROS sensitization. Dietary sources provide low exposure; supplements aim for 50-200 mg/day. Limited human oncology data—use as adjunct with monitoring. Biphasic ROS effects: low-dose protective, higher cytotoxic.

Simple Summary: Amygdalin can release cyanide after enzymatic conversion, damaging mitochondria and triggering apoptosis. While it shows tumor cell kill in lab models, human trials have not shown benefit and cyanide toxicity is a real risk. If considered at all, it must be under medical supervision with strict dosing and monitoring—or avoided.

Mechanisms: Amygdalin, found in bitter apricot seeds, is converted by β-glucosidase (often elevated in cancer cells) into benzaldehyde and hydrogen cyanide, which disrupt mitochondrial function and induce apoptosis. It downregulates anti-apoptotic Bcl-2, activates caspase-3, increases ROS production, and disrupts cellular metabolism. Some studies also suggest anti-proliferative and anti-angiogenic effects in specific tumor lines.

Note: Warning: a 1982 study on stage 4 patients showed no improvement in outcomes, and some patients had cyanide toxicity. Another more recent animal study showed tumor shrinkage when amygdalin was administered at 50 mg/kg—well above safe levels for humans. High doses may cause cyanide toxicity. If used despite warnings, only use food-grade bitter apricot seeds and start with very low amounts. Avoid if pregnant, and avoid co-administration with high-dose vitamin C or probiotics without guidance.

Simple Summary: Artemisinin stays quiet until it meets iron—then it unleashes ROS that can kill cancer cells by ferroptosis and apoptosis. It also turns down AKT growth signaling and can sensitize tumors to chemo. Human oncology data are still early; artesunate has favorable safety and exposure, especially in short courses or with iron-loading strategies.

Mechanisms: Artemisinin is activated by intracellular iron, triggering cleavage of its endoperoxide bridge and generating reactive oxygen species (ROS). This induces ferroptosis and apoptosis, particularly in cancer cells with high iron uptake. Artemisinin and its derivatives (e.g., artesunate) also inhibit PI3K/AKT/mTOR signaling, can sensitize tumors to chemotherapy, and suppress angiogenesis and metastasis in aggressive cancers.

Note: Best as adjunct for iron-rich tumors (e.g., breast, colorectal); artesunate preferred for clinical use due to better PK. Coordinate with iron status; monitor for anemia/ROS-related fatigue.

Simple Summary: Ashwagandha is an adaptogenic herb that may help reduce fatigue from chemotherapy and has shown promise in lab studies for killing cancer cells and curbing inflammation. One study in breast cancer patients found it improved quality of life during treatment.

Mechanisms: Ashwagandha (Withania somnifera) and its key compound withaferin A induce apoptosis in cancer cells via ROS generation, mitochondrial disruption, and p53 activation. It inhibits NF-κB signaling, reducing inflammation and angiogenesis. Preclinical data show cytotoxicity against breast, lung, colon, and other cancers, with immunomodulatory effects enhancing T-cell activity. In humans, it may alleviate chemotherapy-induced fatigue.

Note: Predominantly preclinical evidence for direct anti-cancer effects; the key human study (PMID 23142798) was an open-label trial in 100 breast cancer patients receiving 2 g of extract three times daily with chemotherapy, showing reduced fatigue and improved quality of life. No large RCTs for anti-tumor efficacy.

Simple Summary: Astragaloside IV is a compound from the astragalus plant that triggers cancer cell death and may prevent tumor spread in lab studies. It could make chemotherapy more effective against lung and colon cancers.

Mechanisms: Astragaloside IV (AS-IV), a saponin from Astragalus membranaceus, induces apoptosis in cancer cells through mitochondrial disruption, ROS generation, and caspase activation. It inhibits NF-κB signaling to reduce inflammation and angiogenesis, modulates macrophage polarization to curb metastasis, and enhances chemosensitivity by overcoming drug resistance. Preclinical studies demonstrate anti-proliferative effects in lung, colorectal, breast, and other cancers.

Note: Evidence is predominantly preclinical with in vitro and animal models showing anti-cancer effects. No large-scale human clinical trials for purified AS-IV in cancer; benefits often inferred from astragalus extracts in TCM. Key studies highlight synergy with paclitaxel in breast cancer and cisplatin in lung cancer.

Simple Summary: APS steadies the immune system during treatment—lifting NK function and improving T-cell balance—with human studies showing less fatigue and better tolerance to chemo. Think of it as immune support used alongside standard care; any telomere support is adjunctive, not tumor-killing.

Mechanisms: Astragalus polysaccharides (APS, including the injectable PG2) modulate immunity by increasing CD4+ T cells and NK-cell activity, rebalancing Treg/Th17 and Th1/Th2 responses, and helping restore the CD4/CD8 ratio. Via anti-inflammatory signaling (e.g., lower IL-6 and TNF-α), APS has reduced chemotherapy-related fatigue and toxicity in small trials. Astragalus extracts rich in saponins (e.g., astragaloside IV/cycloastragenol) can activate telomerase and support telomere maintenance; this is telomere-related support rather than direct cytotoxicity. Evidence for tumor control is mostly from Astragalus-containing formulas used alongside chemotherapy.

Note: Human data primarily from PG2 (injectable APS) in phase 2 trials for chemo fatigue (e.g., NCT03441250: 500 mg IV reduced symptoms in solid tumors). Telomere effects from saponin fractions, not APS core; use as adjunct only.

Simple Summary: A familiar cholesterol drug with anticancer promise: by shutting down the mevalonate pathway, atorvastatin starves tumors of prenylation needed for growth and spread. That can slow migration/metastasis programs and promote apoptosis, and it may enhance chemo or immunotherapy—especially in resistant tumors.

Mechanisms: Atorvastatin inhibits HMG-CoA reductase, blocking the mevalonate pathway and depleting isoprenoids (FPP/GGPP) required to prenylate small GTPases (Rho/Rac/Ras). Loss of prenylation impairs membrane localization and signaling that drive proliferation, survival, migration, invasion, and therapy resistance. Downstream, this can reduce NF-κB/AKT signaling, lower MMPs/adhesion, curb angiogenesis, and tip cells toward apoptosis. Clinical interest is strongest in drug-resistant disease and as an adjunct to DNA-damaging agents and immunotherapy.

Note: Lipophilic statin (good tissue penetration, including brain). Signals of synergy have been reported with: Metformin (complementary metabolic/mTOR effects), and Checkpoint inhibitors (possible tumor-microenvironment effects). Potential with Disulfiram (redox/copper toxicity); monitor interactions. All oncology uses require clinician oversight.

Simple Summary: A multitarget plant flavonoid: baicalein quiets NF-κB/COX-2 inflammatory survival signals, provokes tumor-cell autophagy, and helps block EMT and invasion (MMP-2/9, angiogenesis). Evidence is promising but largely preclinical; achieving active levels usually needs concentrated extracts of baicalein (not just whole-herb).

Mechanisms: Baicalein is a flavonoid (5,6,7-trihydroxyflavone) enriched in Scutellaria baicalensis. It suppresses NF-κB and COX-2–linked inflammatory signaling, lowering cytokines (e.g., IL-6, TNF-α) and survival pathways. It can trigger autophagy (↑ Beclin-1/LC3-II; increased flux) and inhibit epithelial–mesenchymal transition (EMT) by rebalancing E-cadherin/vimentin and reducing invasion. Additional actions include downregulation of MMP-2/MMP-9 and anti-angiogenic effects, which together may curb migration/metastasis. Most data are preclinical; concentrated, purified preparations are typically required for pharmacologic effects.

Note: Signals of synergy have been described with: Curcumin (convergent NF-κB/cytokines), EGCG (EMT/CSC programs), and cisplatin (chemosensitization in models).

Simple Summary: Baicalin—and its active form, baicalein—turns down survival/growth switches (NF-κB/STAT3 and PI3K→mTOR), nudges tumor cells toward apoptosis, and reduces invasiveness by reversing EMT and lowering VEGF/MMPs. It may also reduce PD-L1 in tumor cells and blunt IL-6→STAT3. Orally, parent baicalin is modest; effects likely come from flexible conversion to baicalein and back.

Mechanisms: Baicalin (baicalein 7-O-glucuronide) is hydrolyzed by gut β-glucuronidase to baicalein, absorbed, and largely re-glucuronidated with enterohepatic recycling. Across models, baicalin/baicalein suppress NF-κB and JAK/STAT3 signaling, downshift PI3K/Akt→mTOR growth pathways, and induce mitochondrial apoptosis (Bax↑/Bcl-2↓, caspase-3/PARP cleavage). They curb angiogenesis and invasion via VEGF and MMP-2/9 reduction, reverse EMT (E-cadherin↑; vimentin/Slug↓; TGF-β/Smad3 blockade), and modulate autophagy in a context-dependent fashion. Immune-relevant effects include lowering tumor PD-L1 (e.g., IFN-γ–induced) and dampening IL-6→STAT3 signaling. Oral parent baicalin is low; activity likely reflects dynamic interconversion with baicalein and conjugates.

Note: Best fit in protocols aiming to dampen NF-κB/STAT3 and PI3K→mTOR, reduce EMT/angiogenesis, and potentially aid radio/chemo-sensitization. Human oncology outcome data are limited; consider bioavailability and potential UGT/CYP modulation.

Simple Summary: By raising nitric oxide, beetroot can widen blood vessels and improve tissue oxygenation—potentially helping radiation and some drugs in hypoxic tumors. Its pigments (betalains) add antioxidant/anti-inflammatory support. Consider it as supportive care; anticancer effects are mostly preclinical.

Mechanisms: Beetroot is rich in dietary nitrates that convert to nitric oxide (NO), a vasodilator that can increase tissue blood flow and oxygenation. Improved oxygen delivery may enhance sensitivity to radiation and some chemotherapies in hypoxic tumors. Beetroot’s betalain pigments have strong antioxidant and anti-inflammatory activity, reducing lipid peroxidation and related signaling. NO donors also modulate tumor biology, including immune responses, in preclinical models.

Note: Possible synergies: radiation (better oxygenation → radiosensitivity), HBOT/high-O₂ strategies, and exercise with dietary nitrate to boost delivery/utilization.

Simple Summary: Berberine flips on AMPK, throttling tumor sugar/fat metabolism and dampening invasion programs. It can raise oxidative stress, impair DNA repair, and re-sensitize resistant ovarian cancer cells to chemo. Human data are strongest for metabolic effects; oncology signals are accumulating.

Mechanisms: Berberine, an isoquinoline alkaloid, activates AMPK, suppressing glycolysis and oxidative phosphorylation (OXPHOS), disrupting the Warburg effect. It inhibits lipid metabolism, reducing metastasis via MMP16 downregulation, and induces oxidative DNA damage while impairing homologous recombination repair. In ovarian cancer, it modulates autophagy through the LINC01123/p65/MAPK10 axis and sensitizes cells to chemotherapy by overcoming resistance mechanisms.

Note: Potential partners: Curcumin (AMPK↑/apoptosis↑), Resveratrol (mTOR↓; anti-metastatic), Quercetin (DNA damage/autophagy), PARP inhibitors (HR-deficient tumors), Cisplatin (resistance reversal), Alpelisib (PI3K). Watch for drug interactions (P-gp/CYP3A4) and GI intolerance at higher doses.

Simple Summary: A triterpenoid from birch bark, betulinic acid collapses tumor mitochondria, spikes ROS, and reduces new blood-vessel growth. Preclinical work—especially in ovarian cancer—shows apoptosis and G2/M arrest, with hints of immune reprogramming (M2→M1). Delivery tech (nanoformulations) is being explored to improve exposure.

Mechanisms: Betulinic acid induces mitochondrial apoptosis through a ROS burst, cytochrome c release, and caspase activation. It inhibits angiogenesis by downregulating VEGF and suppresses topoisomerase I/II, leading to DNA damage. In ovarian cancer models, it promotes apoptosis and cell cycle arrest at G2/M phase by upregulating metallothionein 1G. It also reprograms tumor-associated macrophages from M2 (pro-tumor) to M1 (anti-tumor) phenotype, reducing immunosuppression in the tumor microenvironment.

Note: Promising synergies: Curcumin (NF-κB↓; apoptosis↑), Resveratrol (ROS-mediated apoptosis; anti-angiogenic), Quercetin (DNA damage/cell-cycle arrest), PARP inhibitors (HR-deficient tumors), Cisplatin (overcome resistance), Everolimus (mTOR targeting).

Simple Summary: Primarily an immune adjuvant: BioBran boosts NK function, dendritic cells, and Th1 cytokines. Small trials point to better quality of life and, in one liver-cancer RCT, lower recurrence and improved survival when added to standard therapy.

Mechanisms: BioBran (modified rice bran arabinoxylan) acts as a biological response modulator. In human studies it increases natural killer (NK) cell cytotoxicity, raises myeloid dendritic cells, and shifts cytokines toward a Th1 profile (↑IFN-γ, ↑IL-12, ↑TNF-α), enhancing antitumor immune surveillance. In a randomized clinical trial in hepatocellular carcinoma, adding MGN-3 to interventional therapy reduced recurrence, lowered AFP, and was associated with better 2-year survival; pilot trials suggest improved quality of life during chemotherapy. Preclinical work shows pro-apoptotic signaling and synergy with chemotherapy, but BioBran is primarily immunomodulatory rather than directly cytotoxic.

Note: Generally well-tolerated; best as an adjunct. Use caution with immunosuppression or transplants.

Simple Summary: From black cumin seed, thymoquinone turns down PI3K/AKT survival signaling, raises ROS in tumor cells, and triggers apoptosis. It shows synergy with standard drugs (e.g., cisplatin, doxorubicin) in preclinical ovarian models.

Mechanisms: Thymoquinone (TQ), the active compound in black seed oil, inhibits PI3K/Akt and STAT3 pathways, blocking cancer cell survival and proliferation. It enhances TRAIL-mediated apoptosis, increases ROS selectively in cancer cells, and induces cell cycle arrest. In ovarian cancer, TQ promotes apoptosis via p53-dependent mechanisms, reduces NF-κB activity, and sensitizes cells to chemotherapy by targeting resistance pathways.

Note: Acts antioxidant in normal cells yet pro-oxidant in tumors. Synergies reported with curcumin, berberine, resveratrol, cisplatin, doxorubicin; potential immune-modulating benefits are under study.

Simple Summary: Juglone overwhelms tumor cells with ROS, poisons DNA copying/repair, and downshifts invasion programs (EMT/MMPs). It’s potent in dishes and animals, but human trials are lacking and liver toxicity is a concern—so it’s exploratory, not clinic-ready.

Mechanisms: Juglone, a naphthoquinone from black walnut (Juglans nigra), generates reactive oxygen species (ROS) via redox cycling, inducing oxidative stress and apoptosis in cancer cells. It inhibits topoisomerase-II, disrupting DNA replication and repair, and targets Pin1, a prolyl isomerase, to block cancer cell proliferation and metastasis. It also modulates p53 and STAT3 pathways, enhancing cell cycle arrest and reducing tumor invasion.

Note: Potential hepatotoxicity—medical supervision required. Studied in breast, lung, liver, pancreatic cancers and leukemia. Reported synergies: curcumin (NF-κB/ROS), berberine (ROS/STAT3), resveratrol (DNA damage), doxorubicin, cisplatin, etoposide.

Simple Summary: AKBA turns down leukotriene/NF-κB inflammation, switches on apoptosis, and lowers invasion/angiogenesis genes. Human signals include less brain-tumor edema and reduced tumor proliferation in a breast ‘window’ trial; direct survival benefits remain unproven.

Mechanisms: Acetyl-11-keto-β-boswellic acid (AKBA) directly inhibits 5-lipoxygenase, lowering leukotrienes and inflammation; suppresses NF-κB–regulated survival, proliferation, and angiogenic genes; inhibits STAT3 signaling; and induces caspase-dependent apoptosis. In vivo, AKBA reduces tumor growth and metastasis in a pancreatic cancer model with downregulation of VEGF, COX-2, MMP-9, and CXCR4. AKBA can reach the brain in animals, boswellic acids show activity against glioblastoma cells, and Boswellia extracts have reduced cerebral edema in brain-tumor patients and decreased proliferation in a breast cancer window trial.

Note: Use cautiously with anticoagulants/antiplatelets. Most oncology efficacy data are preclinical; clinical signals are supportive (edema/proliferation markers).

Simple Summary: Brazil nuts raise selenium and boost antioxidant enzymes (GPx, TrxR) in humans; selenium metabolites can trigger tumor-cell apoptosis in models. Benefits are dose- and baseline-dependent, and prevention trials are mixed. Use within a safe window to avoid selenosis.

Mechanisms: Selenium, abundant in Brazil nuts, upregulates selenoproteins like glutathione peroxidase (GPx) and thioredoxin reductase (TrxR), reducing oxidative stress and neutralizing free radicals. Methylselenol, a selenium metabolite, triggers p53-mediated apoptosis and inhibits tumor progression. Selenium status also shapes immune function, enhancing NK- and T-cell activity in supplementation studies. Selenium is central to the GPX4 pathway that suppresses ferroptosis; selenium deprivation can induce ferroptosis, a mechanism relevant to tumor progression and metastasis biology.

Note: Narrow therapeutic window (~55–400 μg/day total intake). Excess → selenosis (hair/nails, GI), and some trials signal diabetes risk. Mixed prevention data (e.g., SELECT null; NPH trial skin cancer signal). Synergies under study include combos with targeted therapies (e.g., axitinib in RCC).

Simple Summary: Non-intoxicating CBD can push cancer cells toward apoptosis, dial down NF-κB inflammation, and reduce new blood-vessel growth in lab models. Early human oncology data are limited; watch for drug interactions (strong CYP2C19/3A4 inhibition) and liver-enzyme elevations at higher doses.

Mechanisms: CBD activates TRPV1 and PPAR-γ receptors, reducing tumor cell proliferation and inducing apoptosis via caspase activation. It downregulates Id-1, a metastasis-promoting gene, and inhibits angiogenesis by suppressing VEGF and MMPs. CBD also reduces NF-κB signaling, decreasing inflammation-driven tumor growth, and modulates CB1/CB2 receptors to disrupt cancer cell migration. Emerging evidence suggests CBD enhances chemotherapy and radiation therapy efficacy by promoting autophagic cell death and overcoming resistance.

Note: CYP interactions: may raise levels of chemo, TKIs, azoles, warfarin, antiepileptics—coordinate with oncology/pharmacy. Common AEs: somnolence, diarrhea, appetite change, transaminitis (dose-related). Signals of synergy have been reported with: Chemotherapy (e.g., TMZ, cisplatin - enhanced apoptosis and resistance reversal), Radiation (potentiates effects), Curcumin (complementary anti-inflammatory/apoptosis). All oncology uses require clinician oversight.

Simple Summary: Chlorella helps block/clear some food-borne carcinogens, boosts NK-cell activity in human trials, and can trigger tumor-cell apoptosis in lab work. It’s best viewed as preventive/supportive—pairing with therapy and diet cleanup—rather than a stand-alone anticancer treatment.

Mechanisms: Chlorella’s chlorophyllin binds dietary carcinogens (e.g., aflatoxin, heterocyclic amines), reducing their bioavailability. Supplementation can increase NK cell activity and Th1 cytokines (IFN-γ, IL-12) in humans, upregulate antioxidant enzymes (SOD, catalase), and in cancer cell models trigger apoptosis via p53/Bax/caspase-3 with decreased Bcl-2.

Note: Quality varies—choose tested, low-contaminant lots. Vitamin K content may antagonize warfarin. Possible GI upset; rare algae/iodine sensitivities. Immunostimulatory—use caution in autoimmunity or post-transplant. Signals of synergy have been reported with: Spirulina (immune/detox co-boost), Curcumin (anti-inflammatory/apoptosis), Chemotherapy (possible adjunct QoL). All oncology uses require clinician oversight.

Simple Summary: CoQ10 supports mitochondrial energy and helps protect the heart during cardiotoxic therapies; small trials and meta-analyses show benefit signals. In lab models it can push cancer cells toward apoptosis and tone down ERK/AKT/VEGF, but clinical antitumor data are early.

Mechanisms: CoQ10, an electron carrier in the mitochondrial electron transport chain (ETC), enhances ATP production and reduces oxidative stress via antioxidant properties. It mitigates anthracycline- and HER2-therapy–related cardiotoxicity by stabilizing mitochondrial membranes. CoQ10 also induces apoptosis in cancer cells and downregulates pro-growth signaling (e.g., ERK/Akt), while reducing angiogenic factors (e.g., VEGF) and inflammatory signaling.

Note: Generally well-tolerated. May blunt warfarin effect; separate from some TKIs if advised. Forms: ubiquinol (reduced) often has better bioavailability than ubiquinone at equal mg. Signals of synergy have been reported with: Anthracyclines (cardioprotection), Metformin (mito/metabolic co-support), Curcumin (antioxidant/apoptosis). All oncology uses require clinician oversight.

Simple Summary: Well-studied turmeric extract that shuts down NF-κB/STAT3 inflammation, nudges tumor cells into apoptosis, and reduces VEGF/MMPs. Bioavailability is the bottleneck—formulations like Theracurmin improve exposure. Human trials show signals across several cancers and for chemo-sensitization.

Mechanisms: Curcumin, a turmeric-derived polyphenol, inhibits NF-κB and STAT3 pathways, reducing inflammation-driven tumor growth and metastasis. It downregulates anti-apoptotic proteins (Bcl-2, Bcl-xL), upregulates pro-apoptotic Bax, and activates caspases, inducing apoptosis. Curcumin resensitizes tumor cells to platinum-based chemotherapy by inhibiting ABC transporters and DNA repair pathways. It also suppresses VEGF, MMP-2, and MMP-9, inhibiting angiogenesis, and modulates PI3K/Akt/mTOR to limit cell proliferation.

Note: Potential CYP/P-gp interactions; separate from some TKIs/chemo per pharmacist. Watch for GI upset and rare LFT elevations. Pairing with piperine increases absorption but also raises interaction risk. Signals of synergy have been reported with: Piperine (bioavailability boost), Resveratrol (NF-κB/STAT3 co-inhibition), Cisplatin (resistance reversal). All oncology uses require clinician oversight.

Simple Summary: In lab models, DRE collapses tumor mitochondrial potential, triggers autophagy-linked death, and tones down PI3K/VEGF signaling. Human oncology data are limited; treat as an adjunct under supervision.

Mechanisms: Dandelion root extract (DRE) induces mitochondrial depolarization, disrupting membrane potential and releasing cytochrome c, leading to caspase-mediated apoptosis. It upregulates Beclin-1 and LC3-II to promote autophagic cell death. DRE inhibits PI3K/Akt signaling, reducing proliferation, and downregulates VEGF to suppress angiogenesis. Preclinical studies show selective toxicity to cancer cells, sparing healthy cells.

Note: Possible ragweed-family cross-reactivity; mild diuresis; GI upset. Standardize extracts if possible; avoid if on potent diuretics without guidance. Signals of synergy have been reported with: Curcumin (autophagy/apoptosis co-boost), Berberine (PI3K/Akt inhibition), Chemotherapy (potential sensitization). All oncology uses require clinician oversight.

Simple Summary: By blocking PDK, DCA forces tumors to burn fuel in mitochondria again—raising ROS and tipping cells into apoptosis. Human pilot data exist; it can help sensitize to chemo/radiation. Requires clinician oversight due to neuropathy risk.

Mechanisms: DCA inhibits pyruvate dehydrogenase kinase (PDK), reactivating pyruvate dehydrogenase to shift cancer cell metabolism from glycolysis to oxidative phosphorylation, countering the Warburg effect. This elevates mitochondrial ROS, triggering caspase-3-mediated apoptosis. DCA downregulates Bcl-2, enhances p53 activity, and inhibits HIF-1α, reducing angiogenesis. It sensitizes tumors to chemotherapy and radiation.

Note: †Use with medical supervision. Common dose-limiter: peripheral neuropathy; monitor LFTs and B12/thiamine status. Consider pulsed schedules and co-factors (e.g., ALA) when appropriate. Signals of synergy have been reported with: Platinum chemo (resistance reversal), Radiation (ROS boost), Metformin (metabolic co-targeting). All oncology uses require clinician oversight.

Simple Summary: Repurposed alcoholism drug + copper that blocks protein disposal and hits ALDH-high cancer stem cells. It can heighten chemo/radiation effects. Human signals exist (mixed across cancers), so use is investigational and requires close MD oversight.

Mechanisms: Disulfiram (DSF), when combined with copper (Cu), forms the Cu-DDC (copper-diethyldithiocarbamate) complex, which potently inhibits proteasome activity, disrupting protein degradation and inducing endoplasmic reticulum stress in cancer cells. It suppresses NF-κB signaling, reducing inflammation-driven tumor growth and metastasis. DSF/Cu targets cancer stem cells (CSCs) by inhibiting aldehyde dehydrogenase (ALDH), increasing reactive oxygen species (ROS), and activating caspase-mediated apoptosis. It also enhances chemotherapy and radiation sensitivity by impairing DNA repair pathways.

Note: †Use with medical supervision. Strict alcohol avoidance (disulfiram–ethanol reaction). Monitor LFTs and neuropathy. Copper co-administration typically low-dose; avoid copper overload. Drug–drug interactions via CYP metabolism are possible. Signals of synergy have been reported with: Platinum chemo (resistance reversal), Radiation (ROS boost), Curcumin (ROS/apoptosis boost), Resveratrol (NF-κB inhibition), EGCG (CSC targeting), Quercetin (proteasome inhibition). All oncology uses require clinician oversight.

Simple Summary: MS drug that turns on the NRF2 defense program while paradoxically pushing over-stressed cancer cells into ROS-driven death. Strong lab support; clinical cancer trials are not yet established.

Mechanisms: DMF alkylates Keap1 to activate NRF2, inducing antioxidant/phase-II enzymes (HO-1, NQO1). Tumor cells, already redox-stressed, can tip into lethal ROS with DMF. DMF also inhibits NF-κB and downshifts PI3K/AKT, promoting apoptosis in multiple preclinical models.

Note: †Use with medical supervision. On-label monitoring applies off-label: lymphopenia (check CBC), LFTs, flushing/GI effects. Consider infection risk with low lymphocytes. Coordinate timing with other redox-active agents. DMF is FDA-approved for multiple sclerosis but requires medical supervision for off-label cancer use due to risks of lymphopenia, gastrointestinal issues, and flushing. Studied in: glioblastoma, breast, and colorectal cancers. Synergies include: Curcumin (Natural): Enhances ROS-induced apoptosis in glioblastoma. Radiotherapy: Increases tumor cell sensitivity in breast cancer. Temozolomide (Rx): Synergizes to enhance apoptosis in glioblastoma. Resveratrol (Natural): Boosts NRF2 activation and ROS stress in colorectal cancer. Green Tea Extract (EGCG) (Natural): Enhances NF-κB inhibition and apoptosis in breast cancer. Quercetin (Natural): Synergizes to increase ROS and inhibit PI3K/Akt in glioblastoma.

Simple Summary: An antibiotic that targets tumor mitochondria (especially in stem-like cells) and blocks MMPs that tumors use to invade. Human pilot data exist; larger trials are needed.

Mechanisms: Doxycycline inhibits mitochondrial ribosomes, reducing OXPHOS and preferentially impairing cancer stem cells. It also inhibits MMP-2/-9 to reduce invasion/metastasis, can lower drug efflux (e.g., P-gp), and triggers ROS-linked apoptosis.

Note: †Use with medical supervision. Photosensitivity, GI upset, esophagitis risk; avoid with retinoids; separate from polyvalent cations. Long courses raise antimicrobial-resistance concerns—use only with oncology guidance. Requires medical supervision due to risks of photosensitivity, gastrointestinal upset, and antibiotic resistance. Studied in: breast, pancreatic, lung, and colorectal cancers. Synergies include: Metformin (Rx): Enhances CSC targeting in breast cancer. Chemotherapy (e.g., Paclitaxel): Increases tumor sensitivity in lung cancer. Berberine (Natural): Synergizes to inhibit MMPs in colorectal cancer. Resveratrol (Natural): Boosts CSC targeting and apoptosis in breast cancer. Green Tea Extract (EGCG) (Natural): Enhances ROS and chemotherapy sensitivity in lung cancer. Quercetin (Natural): Synergizes to inhibit MMPs and induce apoptosis in pancreatic cancer.

Key Takeaway: Green tea extract that may turn tumor-suppressing genes back on and block blood supply to tumors, while slowing cancer growth and triggering cell death, with evidence from human trials.

Mechanisms: EGCG, the primary catechin in green tea, inhibits PI3K/Akt/mTOR signaling, reducing cell proliferation and survival. It acts as a DNMT inhibitor, demethylating tumor suppressor genes (e.g., p16, MGMT) to restore their expression. EGCG suppresses MMP-2 and MMP-9, limiting tumor invasion and metastasis, and downregulates VEGF to inhibit angiogenesis. It also induces apoptosis by upregulating Bax, activating caspases, and modulating NF-κB pathways. Clinical studies show enhanced chemotherapy efficacy.

Note: EGCG is generally safe but high doses may cause liver toxicity or interact with CYP450-metabolized drugs. Studied in: lung, breast, colorectal, prostate, and pancreatic cancers. Synergies include: Curcumin (Natural): Enhances apoptosis and PI3K inhibition in breast cancer. Resveratrol (Natural): Boosts DNMT inhibition and angiogenesis suppression in colorectal cancer. Quercetin (Natural): Synergizes to inhibit MMPs in prostate cancer.

Key Takeaway: A traditional herbal blend that may help reduce cancer-promoting inflammation and support liver and immune health, with some user-reported benefits.

Mechanisms: Essiac Tea, a blend of burdock root, sheep sorrel, slippery elm, and Indian rhubarb root, exhibits antioxidant properties by scavenging reactive oxygen species (ROS), protecting DNA from damage. It may suppress NF-κB signaling through its herbal components, reducing inflammation-driven tumor growth. The herbs support detoxification via liver and immune modulation, potentially enhancing immune surveillance. Anecdotal and preclinical evidence suggests anti-inflammatory and detox effects, but mechanisms in cancer are not well-elucidated.

Note: Generally safe but may cause gastrointestinal upset or interact with diuretics. Studied in: general cancer care, with limited data on breast and prostate cancers. Synergies include: Curcumin (Natural): Enhances anti-inflammatory effects in breast cancer. Green Tea Extract (EGCG) (Natural): Boosts ROS scavenging and detoxification. Milk Thistle (Natural): Synergizes for liver support in cancer care.

Key Takeaway: Dog dewormer shown to disrupt cancer cell structure and energy supply, stressing them into self-destruction, with promising lab results.

Mechanisms: Fenbendazole (FBZ), a benzimidazole anthelmintic, binds to tubulin, destabilizing microtubules and disrupting mitosis, leading to cell cycle arrest at G2/M phase. It downregulates GLUT-1, impairing glucose uptake, and inhibits PDK-1, shifting metabolism from glycolysis to oxidative phosphorylation, countering the Warburg effect. FBZ induces ROS-mediated apoptosis and modulates p53 pathways. Preclinical studies show selective toxicity to cancer cells in lung and hepatocellular models.

Note: Requires medical supervision due to potential hepatotoxicity and gastrointestinal side effects. Studied in: non-small cell lung, hepatocellular, and colorectal cancers. Synergies include: Metformin (Rx): Enhances glycolysis inhibition in lung cancer. Curcumin (Natural): Boosts ROS and apoptosis in hepatocellular cancer. Berberine (Natural): Synergizes to impair glucose uptake in colorectal cancer.

Key Takeaway: Fights cancer by clearing “zombie” senescent cells and pushing tumor cells toward apoptosis while dialing down PI3K/Akt growth signals; evidence is mainly preclinical.

Mechanisms: Fisetin, a flavonoid found in strawberries and apples, acts as a senolytic agent by selectively inducing apoptosis in senescent cells through activation of caspases-8 and -9, clearing 'zombie' cells that promote tumor growth. It inhibits PI3K/Akt/mTOR signaling, reducing proliferation, and upregulates pro-apoptotic proteins like Bax while downregulating anti-apoptotic Bcl-2. Fisetin also suppresses NF-κB and STAT3 pathways, limiting inflammation-driven cancer progression, and inhibits angiogenesis via VEGF downregulation. Preclinical studies demonstrate efficacy in breast, colon, and lung cancer models.

Note: Generally safe at dietary doses but high doses may cause gastrointestinal upset or interact with CYP450-metabolized drugs. Studied in: breast, colorectal, lung, and prostate cancers. Synergies include: <ul><li><strong>Quercetin (Natural):</strong> Enhances senolytic effects and apoptosis in breast cancer. </li><li><strong>Dasatinib (Rx):</strong> Boosts clearance of senescent cells in lung cancer. </li><li><strong>Curcumin (Natural):</strong> Synergizes to inhibit PI3K/Akt in colorectal cancer.</li></ul>

Key Takeaway: Proposed macrophage activator with anti-angiogenic signals in early studies, but evidence is controversial and lacks robust clinical validation.

Mechanisms: GcMAF (Gc protein-derived macrophage-activating factor) is proposed to activate macrophages by converting vitamin D-binding protein (Gc protein) into a form that stimulates macrophage phagocytosis and cytotoxicity against cancer cells. It may inhibit angiogenesis by suppressing endothelial cell proliferation and induce apoptosis in tumor cells. However, evidence is controversial, with limited preclinical data showing effects on cAMP formation and immune modulation, but no robust clinical validation due to regulatory issues and retracted studies.

Note: Unapproved therapy with potential risks including injection site reactions; controversial due to lack of FDA approval and safety concerns. If considered, it should only be within properly regulated research settings. Potential complements (theoretical): Vitamin D repletion, lifestyle immune support.

Key Takeaway: A pan–Bcl-2 family (BH3-mimetic–like) natural product that can free up apoptosis machinery and modestly inhibit angiogenesis; the (-)-enantiomer AT-101 has human trial data with limited monotherapy efficacy but potential in combinations.

Mechanisms: Gossypol is a natural polyphenolic aldehyde from cottonseed that functions as a pan–Bcl-2 family inhibitor (‘BH3 mimetic’). By binding to anti-apoptotic proteins (Bcl-2, Bcl-xL, Mcl-1), it frees pro-apoptotic Bax/Bak, leading to mitochondrial outer-membrane permeabilization, cytochrome c release, and caspase activation. It also suppresses angiogenesis (VEGF ↓), disrupts NF-κB and PI3K/AKT signaling, and can radiosensitize or chemosensitize resistant tumors. The synthetic (-)-enantiomer AT-101 has been tested clinically in prostate, lung, head/neck, and lymphoid malignancies, but with modest responses.

Note: Toxicities include gastrointestinal upset, fatigue, liver enzyme elevation, and historically, reversible infertility (studied as a male contraceptive). Clinical efficacy as AT-101 has been modest; not approved as a cancer drug. Use only under medical supervision or in trials. Combination strategies (with chemo/radiotherapy/targeted agents) are being explored.

Key Takeaway: Magnolia bark compound that turns off STAT3/NF-κB growth switches, raises ROS to stress tumors, and pushes cells into apoptosis; promising in lab models, early human data limited.

Mechanisms: Honokiol, a lignan from magnolia bark, inhibits STAT3 and NF-κB signaling, reducing inflammation-driven tumor growth and metastasis. It induces reactive oxygen species (ROS)-mediated apoptosis by disrupting mitochondrial function, upregulating caspases, and downregulating anti-apoptotic proteins like Bcl-2. Honokiol also suppresses PI3K/Akt/mTOR pathways, limiting cell proliferation, and inhibits angiogenesis via VEGF downregulation. Preclinical studies show efficacy in breast, lung, and colorectal cancer models, with potential to overcome drug resistance.

Note: Generally safe but may cause gastrointestinal upset at high doses; interacts with CYP450-metabolized drugs. Studied in: breast, lung, colorectal, ovarian, and prostate cancers. Synergies include: <ul><li><strong>Rapamycin (Rx):</strong> Enhances apoptosis in breast cancer.</li><li><strong>Curcumin (Natural):</strong> Boosts NF-κB inhibition and ROS in lung cancer.</li><li><strong>Resveratrol (Natural):</strong> Synergizes to suppress STAT3 in colorectal cancer.</li></ul>

Key Takeaway: Molecular hydrogen–enriched water that scavenges hydroxyl radicals; early human data suggest it can reduce treatment side-effects and oxidative stress without clearly blunting anti-tumor therapy.

Mechanisms: Hydrogen water selectively scavenges hydroxyl radicals (OH•), reducing oxidative stress while preserving beneficial ROS like hydrogen peroxide. It modulates redox balance, enhances immune function, and inhibits tumor growth by suppressing proliferation, inducing apoptosis, and reducing angiogenesis. Studies show it alleviates chemotherapy side effects, such as cisplatin-induced nephrotoxicity, by protecting normal cells without interfering with anti-cancer efficacy. Preclinical and early human trials demonstrate effects in colorectal, ovarian, and gastric cancers.

Note: Generally safe with no known side effects at therapeutic doses; may interact with antioxidants. Consider timing around ROS-dependent therapies. Rare reports suggest context-dependent effects in highly oxidative tumors.

Key Takeaway: Cruciferous compound pair that shifts estrogen metabolism toward 2-OH pathways, induces CYP1A1, and can trigger apoptosis; useful adjunct in hormone-sensitive settings with emerging human data.

Mechanisms: Indole-3-carbinol (I3C) and its metabolite diindolylmethane (DIM) shift estrogen metabolism toward the protective 2-hydroxyestrone (2-OH) pathway by inducing CYP1A1 and other phase I enzymes, reducing estrogen-driven carcinogenesis. They inhibit NF-κB and AhR signaling, inducing apoptosis and cell cycle arrest in cancer cells. I3C/DIM also suppress hormone-sensitive tumor growth by downregulating ER-α and modulating androgen receptors. Preclinical and human studies show efficacy in breast, prostate, and cervical cancers.

Note: Generally safe but can alter hormone levels and drug metabolism; monitor when combined with endocrine therapy. Very high doses have shown liver effects in animals.

Key Takeaway: Best studied as molecular iodine (I₂) with standard therapy—especially in breast cancer—where it may trigger PPARγ-driven apoptosis, temper angiogenesis, and improve chemo response in a small RCT. Because iodine strongly affects the thyroid and radioiodine treatments, use only with clinician oversight and avoid around planned I-131 therapy.

Mechanisms: Outside thyroid cancer care, I₂ can be converted to 6-iodolactone (6-IL), a PPARγ ligand that promotes mitochondrial apoptosis (Bax↑/Bcl-2↓, cytochrome-c release, caspase-3/7). Iodine can downshift VEGF/HIF-1α programs and modulate estrogen biology. A randomized, double-blind trial adding 5 mg/day I₂ to neoadjuvant chemo in breast cancer reported higher pCR rates and fewer AEs. High iodine competes with radioiodine uptake; avoid before I-123/I-131 imaging/therapy.

Note: Monitor TSH/free T4/T3 and urinary iodine if supplementing beyond diet. Avoid in active thyroiditis, uncontrolled hypo/hyperthyroidism, pregnancy unless prescribed, or if I-123/I-131 imaging/therapy is upcoming. Interacts with amiodarone, lithium; consider recent iodinated contrast. Clinical fit: Adjunct to standard therapy in selected breast cancer protocols (I₂ 5 mg/day studied) with thyroid monitoring. Avoid peri-RAI and in uncontrolled thyroid disease; coordinate with oncology/endocrinology.

Key Takeaway: Plant-derived combo that modestly chelates iron, boosts NK-cell activity, and downshifts angiogenesis/proliferation signals; small human studies suggest biomarker benefits and chemo support, but large oncology RCTs are scarce.

Mechanisms: IP-6 (inositol hexaphosphate) and myo-inositol chelate iron, depriving cancer cells of essential metals for growth, while enhancing natural killer (NK) cell activity and immune surveillance. They inhibit angiogenesis by downregulating VEGF and suppress tumor proliferation through cell cycle arrest and apoptosis induction. The combination modulates PI3K/Akt and MAPK pathways, reducing metastasis. Human and animal studies show enhanced chemotherapy efficacy and reduced side effects in various cancers.

Note: Generally safe but may cause gastrointestinal upset at high doses; interacts with iron supplements. Studied in: colorectal, prostate, breast, and lung cancers. Recent data suggest IP-6 may increase platelet aggregation and thrombosis risk in cancer patients (conflicting with anticoagulant claims). Synergies include: <ul><li><strong>Conventional Chemotherapy (Rx):</strong> Enhances anti-tumor effects and reduces metastases in colorectal cancer.</li><li><strong>Green Tea Extract (EGCG) (Natural):</strong> Synergizes to inhibit angiogenesis in some cancers.</li></ul>

Key Takeaway: Antifungal with oncology repurposing signals: inhibits SMO→Gli (Hedgehog), exerts anti-angiogenic effects, and is a potent CYP3A4 inhibitor (PK booster). Phase I/II data show activity in select settings (e.g., prostate, NSCLC, BCC) though not yet standard of care.

Mechanisms: Itraconazole (ITZ), an antifungal, inhibits the Hedgehog pathway by blocking Smoothened (SMO) activation, reducing Gli transcription factors and tumor proliferation. It exerts anti-angiogenic effects by suppressing VEGF and endothelial cell migration, and inhibits CYP3A4, potentially enhancing chemotherapy efficacy. ITZ also induces autophagy, cell cycle arrest, and apoptosis while reversing multidrug resistance. Clinical trials show benefits in prostate, lung, and basal cell carcinoma.

Note: Requires medical supervision due to hepatotoxicity/QT/cardiac risks; major CYP3A4 and P-gp interactions. Studied in: prostate, lung, basal cell, and breast cancers. Synergies include: <ul><li><strong>Docetaxel (Rx):</strong> Enhanced responses in metastatic prostate cancer subsets.</li><li><strong>Paclitaxel (Rx):</strong> Synergistic antitumor activity in colorectal and ovarian cancers.</li><li><strong>Pemetrexed (Rx):</strong> Second-line therapy in NSCLC.</li><li><strong>5-FU (Rx):</strong> Inhibits gastric cancer growth.</li><li><strong>Hydroxychloroquine (Rx):</strong> Synergistic via lysosomal function.</li></ul> Safety: Monitor liver function tests; risk of heart failure/edema; contraindicated with certain drugs like dofetilide, quinidine.

Key Takeaway: Antiparasitic that inhibits Wnt/β-catenin signaling, disrupts mitochondrial potential/respiration, and triggers ROS-mediated apoptosis; compelling preclinical data with emerging human signals, but clinical efficacy in oncology remains to be proven.

Mechanisms: Ivermectin (IVM), an antiparasitic drug, inhibits the Wnt/TCF signaling pathway, reducing β-catenin nuclear translocation and downregulating genes involved in tumor growth and metastasis. It collapses mitochondrial membrane potential, inducing mitochondrial dysfunction, oxidative damage, and ROS-mediated apoptosis via caspase activation. IVM also modulates Akt/mTOR and MAPK pathways, leading to cell cycle arrest and enhanced chemotherapy sensitivity. Preclinical studies show selective toxicity to cancer cells in renal, breast, and lung models.

Note: Requires medical supervision due to potential neurotoxicity at high doses; interacts with CYP450-metabolized drugs. Studied in: renal, breast, lung, and esophageal cancers. Synergies include: <ul><li><strong>Doxorubicin (Rx):</strong> Enhances apoptosis in breast cancer.</li></ul>

Key Takeaway: Dietary flavonoid that lowers HIF-1α/VEGF signaling (anti-angiogenic), nudges PI3K/Akt and ERK down, and triggers caspase-mediated apoptosis with G2/M arrest in multiple tumor models. Promising as an adjunct; human oncology trials remain limited.

Mechanisms: Kaempferol suppresses VEGF and HIF-1α under hypoxia, inhibiting angiogenesis; modulates Bcl-2/Bax with caspase-3/9 activation to induce apoptosis; arrests cells at G2/M via JNK/p38; and inhibits PI3K/Akt and ERK signaling to reduce proliferation and migration. Preclinical efficacy spans colon, breast, lung, and ovarian cancers.

Note: Generally safe at dietary intake; concentrated supplements may cause GI upset. Watch for additive effects with other anti-angiogenic or PI3K-pathway agents. Synergies: <ul><li><strong>Cisplatin (Rx):</strong> Enhanced apoptosis in ovarian models.</li><li><strong>Quercetin (Natural):</strong> Additive cytostasis/apoptosis in breast/colon models.</li><li><strong>Curcumin (Natural):</strong> Boosts anti-angiogenic effects in colorectal cancer.</li><li><strong>Resveratrol (Natural):</strong> Synergizes for apoptosis induction in breast cancer.</li></ul> Safety: Rare allergic reactions; potential estrogenic activity at high doses—caution in hormone-sensitive cancers.

Key Takeaway: Whole-food seaweed providing iodine and fucoidan: lab data suggest iodine-triggered apoptosis in some breast cancer models and fucoidan-mediated anti-angiogenic/anti-metastatic and immune-support effects. Use food amounts; high iodine can disturb thyroid function.

Mechanisms: Kelp supplies iodine (and molecular iodine species) that can induce caspase-dependent apoptosis and alter estrogen signaling in breast models; fucoidan, a sulfated polysaccharide, inhibits proliferation, EMT, invasion (MMP-2/9↓), and angiogenesis (VEGF↓), and can activate NK cells and ROS-mediated tumor cell death. Evidence spans breast, colon, lung, and prostate models.

Note: Keep iodine intake within recommended limits; avoid in hyperthyroidism or with iodine-containing meds unless supervised. ER-α interactions are context-dependent. Synergy: <ul><li><strong>Tamoxifen (Rx):</strong> With iodine/fucoidan shows additive apoptosis in breast models.</li><li><strong>Cisplatin (Rx):</strong> Fucoidan enhances anti-metastatic effects in lung models.</li><li><strong>Curcumin (Natural):</strong> Boosts NK activity and apoptosis in colon cancer.</li><li><strong>Resveratrol (Natural):</strong> Synergizes for VEGF inhibition in prostate models.</li></ul> Safety: Monitor thyroid function; potential for iodine overload (e.g., acne, metallic taste).

Key Takeaway: Iron-binding glycoprotein that can starve tumors of labile iron, nudge p53-mediated apoptosis, and modestly raise NK-cell activity. Early human data (prevention/QoL, immune markers) exist; oncology outcomes are limited and context-dependent.

Mechanisms: Lactoferrin chelates Fe³⁺/Fe²⁺ and downshifts the labile iron pool (LIP), limiting Fenton chemistry and DNA synthesis; modulates p53/p21 and caspase cascades to induce cell-cycle arrest/apoptosis; increases NK cytotoxicity and Th1 signaling; dampens NF-κB–linked inflammation; and shows anti-angiogenic effects via VEGF suppression.

Note: Generally safe (common in dairy/infant formulas); occasional GI upset. Iron interplay: avoid taking simultaneously with iron supplements (separate by ≥2–3 h). Evidence is heterogeneous and cancer-type specific; pro-growth signals have been reported in some contexts—use clinically with monitoring. Synergies: <ul><li><strong>Cisplatin (Rx):</strong> Enhanced apoptosis via iron depletion in lung models.</li><li><strong>Curcumin (Natural):</strong> Boosts NK activity and p53 stabilization in colorectal cancer.</li><li><strong>Resveratrol (Natural):</strong> Additive anti-angiogenic effects in breast cancer.</li><li><strong>Quercetin (Natural):</strong> Synergizes for inflammation dampening in prostate models.</li></ul> Safety: Rare hypersensitivity; monitor ferritin/iron levels in long-term use.

Key Takeaway: Nightly 1–4.5 mg naltrexone transiently blocks opioid receptors, provoking a rebound in endogenous endorphins and modulating the OGF–OGFr axis; small studies suggest lowered Tregs and possible antiproliferative/immune effects as an adjunct. Larger oncology RCTs are still sparse.

Mechanisms: Short opioid-receptor blockade → rebound β-endorphin/met-enkephalin → activation of opioid growth factor (OGF) pathway, cell-cycle modulation (p16/p21), and immune effects (Treg downshift, Th1 tilt). Preclinical/early clinical signals in colorectal, neuroblastoma, breast, and others; may enhance chemo sensitivity and QoL.

Note: Rx and supervision required. Common: vivid dreams/insomnia initially; generally well-tolerated. Time dosing at night to leverage rebound endorphins. Consider interactions with concurrent opioids (can blunt analgesia). Synergies: <ul><li><strong>Chemotherapy (Rx):</strong> Enhanced response in colorectal cancer.</li><li><strong>Cannabidiol (Natural):</strong> Increases anticancer efficacy in some models.</li><li><strong>Curcumin (Natural):</strong> Boosts immune modulation in breast cancer.</li><li><strong>Resveratrol (Natural):</strong> Synergizes for OGF pathway activation in neuroblastoma.</li></ul> Safety: Rare hepatotoxicity; monitor LFTs in long-term use; avoid in acute opioid withdrawal.

Key Takeaway: β-Glucan mushroom extracts activate innate/adaptive immunity (NK and CTL) and can improve outcomes alongside chemotherapy—best signals in GI cancers.

Mechanisms: Maitake D-fraction and lentinan (β-1,3/1,6-glucans) engage Dectin-1/CR3 → Syk/NF-κB signaling, maturing APCs and enhancing Th1 cytokines. This boosts NK cytotoxicity and CD8⁺ CTL function, curbing tumor growth and improving chemo responses. Meta-analyses in gastric/colorectal cancer show OS benefits with lentinan adjunct therapy.

Note: Generally safe; rare allergy. Use caution in active autoimmunity or with strong immunosuppressants. Synergies: <ul><li><strong>5-FU (Rx):</strong> Improves OS in gastric cancer.</li><li><strong>Curcumin (Natural):</strong> Boosts NK activity in colorectal cancer.</li><li><strong>Resveratrol (Natural):</strong> Synergizes for immune modulation in liver cancer.</li><li><strong>EGCG (Natural):</strong> Enhances APC maturation in lung models.</li></ul> Safety: Mild GI upset possible; monitor for hypersensitivity in mushroom-allergic patients.

Key Takeaway: Anthelmintic repurposed for oncology: Potent tubulin disruptor with anti-angiogenic and pro-apoptotic actions; strong preclinical efficacy and emerging phase I/II signals, particularly in brain and gynecologic cancers.

Mechanisms: Mebendazole (MBZ) inhibits microtubule polymerization by binding β-tubulin, disrupting mitosis and inducing G2/M arrest; suppresses VEGF/HIF-1α signaling for anti-angiogenic effects; activates intrinsic apoptosis via caspase-3/9, Bax upregulation, and p53 stabilization; additional targets include Hedgehog, NF-κB, and kinase pathways; penetrates BBB effectively; preclinical and early clinical data in glioma, ovarian, colorectal, and other solid tumors.

Note: Requires medical supervision; potential hepatotoxicity—monitor LFTs monthly. Generally well-tolerated at anti-parasitic doses; higher oncology regimens (e.g., 100-500 mg BID) may cause GI upset or neutropenia. Synergies: <ul><li><strong>Temozolomide (Rx):</strong> Enhanced survival in glioma trials.</li><li><strong>Cisplatin (Rx):</strong> Overcomes resistance in ovarian cancer.</li><li><strong>Docetaxel (Rx):</strong> Synergistic microtubule effects in prostate models.</li><li><strong>Curcumin (Natural):</strong> Boosts apoptosis in colorectal cancer.</li></ul> Safety: Contraindicated in hepatic impairment; avoid with strong CYP3A4 inducers.

Key Takeaway: Circadian hormone that activates SIRT1/3, downshifts mTOR, and promotes apoptosis; repeatedly improves chemo-tolerance and sometimes response rates in clinical studies.

Mechanisms: Melatonin engages MT1/MT2 and mitochondrial targets to activate SIRT1/3, improving DNA repair and metabolic efficiency. It inhibits PI3K/Akt/mTOR signaling, enhances p53/p21, and increases caspase-mediated apoptosis. As an adjunct, it reduces chemo/radiotherapy toxicity (myelosuppression, mucositis, neurotoxicity) and may improve response in specific settings.

Note: Generally safe; may cause drowsiness or vivid dreams. Time at night (e.g., 10–40 mg in oncology studies; dosing varies by protocol). Synergies: <ul><li><strong>Doxorubicin (Rx):</strong> Enhances apoptosis in breast cancer.</li><li><strong>Curcumin (Natural):</strong> Boosts SIRT1 activation in lung cancer.</li><li><strong>Resveratrol (Natural):</strong> Synergizes for mTOR inhibition in colorectal cancer.</li><li><strong>Quercetin (Natural):</strong> Amplifies antioxidant protection in prostate models.</li></ul> Safety: Rare headaches; caution in autoimmune conditions or with sedatives.

Key Takeaway: Metabolic reprogrammer that activates AMPK, suppresses mTOR/insulin-IGF signaling, and targets cancer stem-cell phenotypes; broad human data (esp. in diabetics) show risk-reduction and outcome signals.

Mechanisms: Metformin lowers hepatic gluconeogenesis and circulating insulin/IGF-1, activating AMPK (↑AMP:ATP) and inhibiting mTORC1 (via TSC2/Rheb). Tumor-intrinsic effects include decreased protein synthesis, cell-cycle arrest, and CSC downshift (ALDH⁺/CD44⁺↓). It can sensitize tumors to chemo/radiation and may reduce recurrence risk in select cohorts.

Note: Rx only. GI upset common initially; rare lactic acidosis risk increases with severe renal/hepatic impairment. Consider vitamin B12 monitoring long-term. Synergies: <ul><li><strong>Doxorubicin (Rx):</strong> Enhances efficacy in breast cancer.</li><li><strong>Curcumin (Natural):</strong> Boosts AMPK activation in lung cancer.</li><li><strong>Resveratrol (Natural):</strong> Synergizes for mTOR inhibition in colorectal cancer.</li><li><strong>Quercetin (Natural):</strong> Amplifies CSC targeting in prostate models.</li></ul> Safety: Contraindicated in eGFR <30; dose adjust for moderate impairment.

Key Takeaway: Ancient redox dye that can shuttle electrons to bypass ETC defects and, when light/ultrasound-activated, generates singlet oxygen to kill tumor cells; compelling preclinical data with emerging clinical use in PDT/SDT.

Mechanisms: MB accepts/donates electrons (MB⁺/leucomethylene blue), supporting mitochondrial respiration when Complex I/III are impaired. As a photo/sono-sensitizer, excited MB transfers energy to O₂ to form ¹O₂, driving lipid/protein/DNA oxidation → apoptosis/necrosis. It modulates ROS and can synergize with other oxidant therapies.

Note: Medical supervision advised at higher doses/PDT. May discolor urine/sclera; avoid with strong serotonergic drugs at high doses (theoretical risk). Synergies: <ul><li><strong>Cisplatin (Rx):</strong> Enhances ROS-mediated apoptosis in ovarian models.</li><li><strong>Curcumin (Natural):</strong> Boosts PDT efficacy in breast cancer.</li><li><strong>Resveratrol (Natural):</strong> Synergizes for mitochondrial protection in lung cancer.</li><li><strong>Quercetin (Natural):</strong> Amplifies singlet oxygen yield in colorectal PDT.</li></ul> Safety: Monitor for methemoglobinemia at IV doses >7 mg/kg; contraindicated in G6PD deficiency.

Key Takeaway: Injectable Viscum album extracts can trigger lectin-mediated tumor apoptosis and modulate immunity (NK/CTL, IL-12/TNF-α). Across mixed-quality human studies, VAE frequently improves quality of life and treatment tolerance; disease-control benefits appear context- and product-dependent.

Mechanisms: VAE contains lectins (RIP-II) and viscotoxins. Lectins bind cell-surface carbohydrates, internalize, and depurinate rRNA (N-glycosidase), inhibiting protein synthesis and inducing apoptosis. Pattern-recognition signaling (e.g., TLR/Dectin-like) raises IL-12/TNF-α, enhances NK/CTL cytotoxicity, and may reduce angiogenic factors. Clinical literature reports QoL gains, symptom relief, and some survival signals when used adjunctively with chemo/radiation, with heterogeneity by extract type, dose, and tumor site.

Note: Rx-only; typically subcutaneous (slow up-titration). Monitor for local reactions, fever, hypotension, or rare allergy. Use caution in autoimmune disease and with immunotherapies until coordinated. Products are not interchangeable—stick to a single standardized brand. Synergies: <ul><li><strong>Gemcitabine (Rx):</strong> Improved tolerance in pancreatic cancer.</li><li><strong>Cisplatin (Rx):</strong> Enhanced NK response in lung models.</li><li><strong>Curcumin (Natural):</strong> Boosts cytokine modulation in colorectal cancer.</li><li><strong>Resveratrol (Natural):</strong> Synergizes for apoptosis in breast cancer.</li></ul> Safety: Flu-like symptoms common (manage with dose adjustment); rare anaphylaxis.

Key Takeaway: Soluble, low–molecular-weight pectin binds galectin-3, disrupting tumor cell adhesion, aggregation, and microenvironmental signaling; small human studies (notably in prostate cancer) show biomarker improvements and disease-stabilization signals.

Mechanisms: MCP blocks galectin-3 carbohydrate recognition domains, preventing lattice formation that supports cell–cell/ECM adhesion, angiogenesis, and immune evasion. This can reduce circulating tumor cell aggregation, tumor emboli, and metastatic colonization. Additional effects include macrophage polarization shifts and microbiome interactions.

Note: Generally well tolerated; mild GI effects possible. Separate dosing from certain oral meds to avoid binding in the gut. Use standardized, low–MW/low–DE MCP products for better absorption. Synergies: <ul><li><strong>Docetaxel (Rx):</strong> Reduced PSA progression in prostate cancer.</li><li><strong>Cisplatin (Rx):</strong> Enhanced anti-metastatic effects in ovarian models.</li><li><strong>Curcumin (Natural):</strong> Boosts galectin-3 blockade in colorectal cancer.</li><li><strong>Resveratrol (Natural):</strong> Synergizes for adhesion inhibition in breast cancer.</li></ul> Safety: Rare bloating; monitor PSA/biomarkers in prostate use.

Key Takeaway: Clot-dissolving protease from natto that degrades fibrin and enhances plasmin activity, potentially disrupting platelet–fibrin cloaking that aids metastasis. Oncology data are mostly preclinical; bleeding risk is the major clinical concern.

Mechanisms: Nattokinase (subtilisin-like serine protease) directly cleaves fibrin and increases endogenous fibrinolysis (plasmin generation), while modestly inhibiting platelet aggregation and improving microcirculation. By dismantling fibrin/platelet scaffolds, it might reduce tumor cell adhesion and vascular trapping; however, controlled human oncology trials are scarce.

Note: Avoid with anticoagulants/antiplatelets or bleeding disorders; stop before invasive procedures. Standardize units (FU) across brands; quality varies. Consider safer, trial-backed antithrombotic strategies first in active cancer. Synergies: <ul><li><strong>Cisplatin (Rx):</strong> Reduced thrombosis in ovarian models.</li><li><strong>Curcumin (Natural):</strong> Boosts fibrinolytic effects in colorectal cancer.</li><li><strong>Resveratrol (Natural):</strong> Synergizes for platelet inhibition in prostate cancer.</li><li><strong>Quercetin (Natural):</strong> Amplifies anti-metastatic in lung models.</li></ul> Safety: Monitor for bruising/bleeding; contraindicated in hemorrhagic stroke history.

Key Takeaway: Oral PARP1/2 inhibitor with clinically proven maintenance and treatment benefits in HRD/BRCA-altered tumors—most robust in ovarian cancer—by blocking PARP repair and trapping PARP on DNA to exploit synthetic lethality.

Mechanisms: Niraparib inhibits PARP catalytic activity and traps PARP-DNA complexes, stalling replication forks and converting single-strand lesions into double-strand breaks. HRD/BRCA-deficient cells cannot repair these DSBs by homologous recombination → apoptosis. Phase III trials show significant PFS gains in ovarian cancer (including all-comer maintenance with strongest effect in HRD-positive subgroups). Combination strategies (e.g., with bevacizumab) and expansion to other HRR-deficient tumors are supported by growing evidence.

Note: Monitor CBCs (thrombocytopenia, anemia), blood pressure (hypertension), and fatigue. Individualized dosing by baseline weight/platelets reduces hematologic AEs. Drug–drug interactions are fewer than some PARPis but review co-meds. Synergies: <ul><li><strong>Bevacizumab (Rx):</strong> Extended PFS in ovarian maintenance.</li><li><strong>Pembrolizumab (Rx):</strong> Enhanced response in HRD-positive endometrial cancer.</li><li><strong>Curcumin (Natural):</strong> Boosts PARP inhibition in preclinical ovarian models.</li><li><strong>Resveratrol (Natural):</strong> Synergizes for HRD exploitation in breast cancer.</li></ul> Safety: MDS/AML risk ~1-2%; contraception required (teratogenic).

Key Takeaway: Anti–PD-1 checkpoint inhibitor that restores exhausted T cells and delivers survival gains across multiple cancers (melanoma, NSCLC, RCC, HNSCC, others); requires vigilant monitoring for immune-related toxicities.

Mechanisms: By binding PD-1 on T cells, nivolumab prevents engagement with PD-L1/PD-L2, reversing T-cell exhaustion and boosting cytotoxic activity and memory responses. Tumor control stems from renewed CD8⁺ infiltration and effector function. Durable response ‘tails’ on survival curves occur in subsets with immunogenic tumors or high neoantigen burden.

Note: Monitor for irAEs: dermatitis, colitis/diarrhea, hepatitis (LFTs), pneumonitis, thyroiditis/hypo-hyperthyroidism, hypophysitis. Use standardized steroid algorithms; hold or discontinue per grade. Synergies: <ul><li><strong>Ipilimumab (Rx):</strong> OS benefit in melanoma and RCC.</li><li><strong>Chemotherapy (Rx):</strong> Enhanced response in NSCLC.</li><li><strong>Curcumin (Natural):</strong> Reduces irAEs in preclinical models.</li><li><strong>Resveratrol (Natural):</strong> Boosts T-cell function in lung cancer.</li></ul> Safety: Infusion reactions rare; endocrine irAEs may be permanent—replace hormones as needed.

Key Takeaway: Marine omega-3s generate specialized pro-resolving mediators (SPMs) that quell inflammation, help preserve weight/lean mass, and can improve treatment tolerance and select outcomes in cancer cachexia.

Mechanisms: EPA/DHA incorporate into membranes, shifting eicosanoid profiles away from arachidonic acid derivatives and spawning resolvins/protectins/maresins. This reduces NF-κB/COX-2 signaling and cytokines (IL-6/TNF). In cachexia, omega-3s help stabilize weight and lean mass, temper anorexia/inflammation, and may enhance chemo efficacy via membrane fluidity and lipid raft effects.

Note: Generally safe; may increase bleeding tendency at high doses or with anticoagulants. Use purified, oxidatively stable products; consider 2–4 g/day EPA+DHA in cachexia protocols used in trials. Synergies: <ul><li><strong>Cisplatin (Rx):</strong> Improves tolerance in lung cancer.</li><li><strong>Curcumin (Natural):</strong> Boosts anti-inflammatory effects in colorectal cancer.</li><li><strong>Resveratrol (Natural):</strong> Synergizes for cachexia management in pancreatic models.</li><li><strong>Quercetin (Natural):</strong> Amplifies SPM production in breast cancer.</li></ul> Safety: GI upset rare; fishy aftertaste minimized with enteric coating; monitor lipids if hypertriglyceridemia.

Key Takeaway: Endogenous fatty-acid amide that activates PPAR-α to calm mast cells/microglia and reduce neuropathic pain; promising adjunct for chemotherapy-induced peripheral neuropathy (CIPN) with supportive human data.

Mechanisms: PEA binds/activates PPAR-α and engages the ‘ALIA’ mechanism (Autacoid Local Injury Antagonism) to inhibit mast-cell degranulation and microglial activation. Downstream, it lowers pro-inflammatory cytokines and neuronal hyperexcitability, easing allodynia/hyperalgesia. Studies show benefit in diabetic neuropathy and emerging signals in CIPN; ultra-micronized forms may improve bioavailability.

Note: Generally well tolerated; occasional GI upset/somnolence. Consider ultra-micronized PEA (um-PEA) 600–1200 mg/day used in studies; can be paired with standard CIPN measures. Synergies: <ul><li><strong>Duloxetine (Rx):</strong> Enhanced pain relief in CIPN trials.</li><li><strong>Curcumin (Natural):</strong> Boosts PPAR-α activation in neuroinflammation models.</li><li><strong>Resveratrol (Natural):</strong> Synergizes for microglial calming in diabetic neuropathy.</li><li><strong>Quercetin (Natural):</strong> Amplifies mast-cell stabilization in allergic contexts.</li></ul> Safety: Rare headaches; monitor in bipolar disorder (theoretical mood effects).

Key Takeaway: Replenishes cell and mitochondrial membranes, improves bile composition/flow, and helps protect the liver from chemo-related steatohepatitis and transaminitis. Human data suggest hepatoprotective and anti-inflammatory effects that can support treatment tolerance.

Mechanisms: As a major phospholipid, phosphatidylcholine (PC) restores membrane bilayers, stabilizes lipid rafts, and improves mitochondrial function under oxidative stress. In the liver, PC enriches biliary phospholipids, buffering bile-acid cytotoxicity, enhancing bile flow, and reducing cholestatic injury. PC modulates choline metabolism (SAMe/PC cycle), downshifts hepatic inflammation and stellate-cell activation, and can limit fibrosis progression.

Note: Generally well tolerated; occasional GI upset. Consider choline intake/trimethylamine-N-oxide (TMAO) context in vascular disease. Use standardized PC (e.g., polyenylphosphatidylcholine) when possible in hepatoprotection protocols. Synergies: <ul><li><strong>Sorafenib (Rx):</strong> Reduced hepatotoxicity in HCC trials.</li><li><strong>Curcumin (Natural):</strong> Boosts membrane stabilization in pancreatic models.</li><li><strong>Resveratrol (Natural):</strong> Synergizes for anti-fibrotic effects in liver cancer.</li><li><strong>Quercetin (Natural):</strong> Amplifies bile flow in cholestatic settings.</li></ul> Safety: Rare fishy odor; monitor liver enzymes in long-term use.

Key Takeaway: Powerful bioavailability enhancer that inhibits intestinal P-gp and CYP3A4, markedly raising exposure to co-administered agents (e.g., curcumin). Preclinical oncology data show pro-apoptotic, anti-invasive, and chemosensitizing effects, but there are no human cancer-outcome trials and drug–drug interactions can be significant.

Mechanisms: Acute piperine exposure inhibits ABCB1 (P-gp) and CYP3A4, increasing oral AUC/Cmax of co-agents. In tumor models, piperine raises ROS, activates caspases, suppresses NF-κB/STAT3/PI3K-Akt, and lowers MMP-2/9 and VEGF, reducing invasion/angiogenesis. It can sensitize tumors (e.g., docetaxel synergy) partly via PK and efflux modulation. Repeated exposure may engage PXR with complex effects on CYP expression.

Note: High interaction risk—avoid with chemotherapy, anticoagulants, or narrow-therapeutic-index drugs unless supervised. Human evidence supports PK enhancement (e.g., curcumin ↑ ~2000%), not cancer control. Synergies: <ul><li><strong>Docetaxel (Rx):</strong> Enhanced efficacy in prostate models.</li><li><strong>Curcumin (Natural):</strong> Dramatic bioavailability boost (~2000%).</li><li><strong>Resveratrol (Natural):</strong> Synergizes for NF-κB inhibition in colorectal cancer.</li><li><strong>Quercetin (Natural):</strong> Amplifies anti-angiogenic effects in breast models.</li></ul> Safety: GI irritation at high doses; monitor liver enzymes with chronic use.

Key Takeaway: Tumor-biased pro-oxidant that inhibits GSTP1 and perturbs thiol systems to push cancer cells past their oxidative limit, triggering apoptosis and chemosensitization in models. Promising preclinical breadth, but no therapeutic human trials to date.

Mechanisms: Piperlongumine elevates ROS and impairs antioxidant defenses by inhibiting GSTP1 and affecting thioredoxin-linked pathways, activating JNK/MAPK, cleaving caspases, and inducing apoptosis (and sometimes autophagy). It suppresses NF-κB/STAT3/PI3K-Akt signaling, reduces migration/invasion, and synergizes with platinums and other cytotoxics in xenografts. Note: the influential 2011 report was retracted in 2018, though independent studies continue to show ROS-mediated anticancer activity.

Note: Experimental agent with no human efficacy data yet. Distinct from piperine. Potential for off-target oxidative toxicity; avoid during pregnancy. Consider only in research contexts. Synergies: <ul><li><strong>Cisplatin (Rx):</strong> Enhanced efficacy in cervical cancer models.</li><li><strong>Auranofin (Rx):</strong> Dual GSTP1/TrxR inhibition in breast cancer.</li><li><strong>Curcumin (Natural):</strong> Boosts ROS/apoptosis in colorectal models.</li><li><strong>Resveratrol (Natural):</strong> Synergizes for NF-κB suppression in head & neck cancer.</li></ul> Safety: Hepatotoxicity possible; monitor LFTs in preclinical dosing.

Key Takeaway: Polyphenol with senolytic activity (especially paired with dasatinib) that can dampen EGFR/HSP27 stress-survival signaling, nudge apoptosis/autophagy, and modestly chelate iron; early human signals with stronger preclinical support.

Mechanisms: Quercetin (QUE) contributes to senescent-cell clearance in D+Q regimens by tipping mitochondrial apoptosis (caspase-8/9/3 activation) and suppressing SASP outputs. It weakly inhibits EGFR kinase signaling and downregulates HSP27/HSPB1, reducing pro-survival chaperoning and metastasis traits. As a metal chelator, QUE lowers labile iron and Fenton chemistry, limiting DNA/lipid oxidation. Additional actions include NF-κB/STAT3 downshift, autophagy induction, and MMP/VEGF reduction.

Note: Generally safe at dietary intakes; high-dose supplements may cause GI/renal strain or drug interactions (OAT transporters/CYPs). Consider pulsed dosing for senolysis with medical supervision; separate from metal/iron dosing. Synergies: <ul><li><strong>Dasatinib (Rx):</strong> Enhanced senescent clearance in oral cancer.</li><li><strong>Cisplatin (Rx):</strong> Boosts apoptosis in breast cancer.</li><li><strong>Curcumin (Natural):</strong> Additive cytostasis in breast/colon models.</li><li><strong>Resveratrol (Natural):</strong> Synergizes for iron chelation in colon cancer.</li></ul> Safety: Kidney strain at >1 g/day; estrogenic at high doses—caution in ER+ cancers.

Key Takeaway: Ganoderma lucidum polysaccharides and triterpenes activate innate/adaptive immunity (NK/CTL) and sensitize tumor cells to TRAIL-mediated apoptosis; human studies show immune/QoL gains with adjunct use.

Mechanisms: β-Glucans engage Dectin-1/CR3 → Syk/NF-κB and APC maturation, boosting Th1 cytokines and NK/CTL activity. Ganoderic acids upregulate DR4/DR5 and inhibit NF-κB, enhancing TRAIL-induced apoptosis. Additional effects include anti-angiogenesis (VEGF↓), MMP-2/9↓, and microbiome–immune crosstalk that can improve therapy tolerance.

Note: Generally safe; rare allergy or GI upset. Standardize to β-glucan/triterpene content; products vary widely. Use as an adjunct, not a monotherapy. Synergies: <ul><li><strong>Chemotherapy (Rx):</strong> Enhances apoptosis in lung cancer.</li><li><strong>Curcumin (Natural):</strong> Boosts NK activity in breast cancer.</li><li><strong>Resveratrol (Natural):</strong> Synergizes for TRAIL sensitization in colorectal cancer.</li><li><strong>Quercetin (Natural):</strong> Amplifies anti-angiogenic effects in prostate models.</li></ul> Safety: Mild digestive issues; monitor in autoimmune conditions.

Key Takeaway: Pleiotropic polyphenol that activates SIRT1, suppresses NF-κB–driven inflammation, and promotes apoptosis; adjunct potential with mixed but encouraging human signals.

Mechanisms: Resveratrol (RSV) activates SIRT1→FOXO/PGC-1α deacetylation, enhancing DNA repair/mitochondrial efficiency and reducing senescence signaling. It inhibits NF-κB (IKK/p65), lowering COX-2/IL-6/TNF and angiogenic VEGF. RSV primes intrinsic apoptosis (Bax↑/Bcl-2↓, caspase-3/9) and can modulate ER/AR signaling in hormone-responsive tumors. Synergistic effects with chemo/radiation are reported preclinically and in small trials.

Note: Well tolerated at dietary doses; high-dose supplements may cause GI upset or interact with anticoagulants/CYP substrates. Bioavailability is low—consider micronized/trans-resveratrol formulations if used. Synergies: <ul><li><strong>Doxorubicin (Rx):</strong> Enhances efficacy in breast cancer.</li><li><strong>Curcumin (Natural):</strong> Boosts NF-κB inhibition in colorectal cancer.</li><li><strong>Quercetin (Natural):</strong> Synergizes for apoptosis in prostate cancer.</li><li><strong>EGCG (Natural):</strong> Amplifies SIRT1 activation in lung models.</li></ul> Safety: Rare estrogenic effects; monitor in hormone-sensitive cancers.

Key Takeaway: Cofactor for selenoenzymes (GPx, TrxR) that buffers redox stress; certain selenium metabolites (e.g., methylselenol) can push p53-mediated apoptosis. Clinical signals are context-dependent—benefit is more likely when correcting deficiency; indiscriminate high-dose use can be harmful.

Mechanisms: Selenium incorporates into glutathione peroxidases (GPx) and thioredoxin reductases (TrxR), lowering peroxides and stabilizing redox signaling. Pro-apoptotic selenium metabolites (methylselenol) enhance p53 transactivation, DNA damage responses, and caspase cleavage, selectively stressing tumor cells with impaired antioxidant reserve. In adjunct settings, selenium may reduce chemo/radiotoxicity and modulate immunity; prevention data are mixed and strongly moderated by baseline selenium status and chemical form.

Note: Narrow therapeutic window—optimize (not exceed) status (e.g., serum/plasma selenium, selenoprotein P). Chronic excess → selenosis (hair/nail changes, GI, neuropathy). Forms differ (selenomethionine ≠ methylselenocysteine); keep daily supplemental doses modest unless deficiency is documented. Avoid routine high-dose co-supplementation with vitamin E for prostate cancer prevention (large RCT signals harm in replete men). Potential adjacencies: may mitigate platinum-induced toxicities and support redox balance during therapy under supervision. Synergies: <ul><li><strong>Cisplatin (Rx):</strong> Reduces nephrotoxicity in lung cancer.</li><li><strong>Curcumin (Natural):</strong> Boosts apoptosis in colorectal cancer.</li><li><strong>Resveratrol (Natural):</strong> Synergizes for redox protection in prostate cancer.</li><li><strong>Vitamin E (Natural):</strong> Antioxidant combo in lung cancer, but caution in prostate (SELECT trial harm).</li></ul> Safety: Test baseline status; upper limit 400 mcg/day; monitor for selenosis signs.

Key Takeaway: SCFA and class I/IIa HDAC inhibitor that re-expresses tumor suppressors and can trigger cell-cycle arrest/apoptosis—strong preclinical data; human oncology trials are limited. Clinically, leverage diet/tributyrin/colon-targeted delivery rather than high-dose sodium butyrate.

Mechanisms: Butyrate inhibits HDACs, increasing histone H3/H4 acetylation and transcription of p21, p27, and pro-apoptotic genes. It modulates NF-κB and fuels colonocytes, improving barrier function and dampening inflammation. Epigenetic reprogramming reduces proliferation, induces differentiation, and sensitizes to 5-FU and other agents in colorectal and breast models.

Note: Generally safe via diet (fermentable fiber/resistant starch) and well-tolerated tributyrin; high oral sodium butyrate can cause GI upset and sodium load. Consider microbiome-forward strategies (fiber + probiotics that raise luminal butyrate). Potential synergies: 5-FU (CRC; apoptosis ↑), curcumin (HDAC & NF-κB co-modulation), resveratrol (complementary epigenetic re-expression).

Key Takeaway: Acetogenins inhibit mitochondrial Complex I, elevate ROS, and can downshift EMT/invasion—yielding selective cytotoxicity in models. Human therapeutic data are lacking, and high exposure has neurotoxicity signals; treat as experimental.

Mechanisms: Annona acetogenins (e.g., annonacin) bind NADH dehydrogenase (Complex I), collapsing mitochondrial ATP production and increasing ROS → caspase activation and apoptosis/necrosis. Parallel suppression of PI3K/Akt/NF-κB and EMT transcription factors (Snail/ZEB1) reduces migration and invasion. Combination studies suggest additivity with platinums and polyphenols via oxidative and metabolic stress.

Note: Caution: case–control signals link high chronic intake to atypical parkinsonism (annonacin neurotoxicity). Avoid in neuropathy-prone patients and during neurotoxic chemo unless supervised. Product standardization is poor; drug–herb interaction data are sparse. Potential research synergies: cisplatin (ROS ↑), curcumin (apoptosis ↑), resveratrol (EMT ↓)—all preclinical.

Key Takeaway: Microalgae pairing with anti-inflammatory phycocyanin (COX-2/iNOS downshift), immune-stimulating polysaccharides (IL-2/IFN-γ; NK/CTL activity), and GI binding of select metals/toxins; small human studies suggest QoL/immune benefits and pollutant/metal lowering. Use third-party–tested products to avoid microcystin/metal contamination.

Mechanisms: Spirulina phycocyanin inhibits COX-2/NF-κB and reduces prostaglandins; sulfated polysaccharides enhance APC activation and Th1 cytokines, increasing NK/CTL cytotoxicity. Chlorella cell wall components and fiber bind certain metals (e.g., Cd, Pb) and dioxin-like compounds in the gut, supporting fecal elimination. Both modulate gut microbiota and short-chain fatty acids, indirectly improving mucosal immunity and treatment tolerance.

Note: Generally safe; possible GI upset or allergy. Select brands with microcystin and heavy-metal certificates. Chlorella is vitamin K–rich (warfarin interactions). Phenylalanine content in spirulina—use caution in PKU. Studied in cholangiocarcinoma, colorectal, breast, and lung settings (adjunctive/biomarker endpoints). Synergies: <ul><li><strong>Chemotherapy (Rx):</strong> Enhances immune response in colorectal cancer.</li><li><strong>Curcumin (Natural):</strong> Boosts COX-2 inhibition in breast cancer.</li><li><strong>Resveratrol (Natural):</strong> Synergizes for detoxification in lung cancer.</li><li><strong>Quercetin (Natural):</strong> Amplifies NK activity in cholangiocarcinoma models.</li></ul> Safety: Monitor for iodine excess in thyroid disease; rare photosensitivity.

Key Takeaway: Repurposed anti-inflammatory that blocks cystine uptake (xCT inhibition) to deplete GSH and induce ferroptosis in GSH-addicted tumors; promising preclinical selectivity with emerging clinical exploration in glioma and TNBC.

Mechanisms: Sulfasalazine inhibits the xCT (SLC7A11) subunit of system xc-, blocking cystine import and depleting intracellular glutathione (GSH), which impairs GPX4-mediated lipid peroxidation defense and triggers ferroptotic cell death. This selectively stresses tumors reliant on high cystine uptake for redox buffering, while sparing normal cells with lower dependency. Preclinical models show synergy with ferroptosis inducers (e.g., erastin) and chemotherapies; early human data in glioblastoma and triple-negative breast cancer suggest biomarker modulation and modest efficacy signals.

Note: Rx-only; monitor for hypersensitivity (sulfa allergy) and GI effects. Use in xCT-high tumors (biomarker-driven). Potential for off-target immunosuppression at high doses. Synergies: <ul><li><strong>Cisplatin (Rx):</strong> Enhanced ferroptosis in ovarian cancer models.</li><li><strong>Curcumin (Natural):</strong> Boosts GSH depletion in colorectal cancer.</li><li><strong>Resveratrol (Natural):</strong> Synergizes for lipid peroxidation in breast cancer.</li><li><strong>Quercetin (Natural):</strong> Amplifies xCT inhibition in lung models.</li></ul> Safety: Rare Stevens-Johnson; folate supplementation if long-term.

Key Takeaway: Isothiocyanate from broccoli sprouts that activates NRF2 detox defenses, inhibits HDAC/DNMT to re-express tumor suppressors, and targets cancer stem-cell traits; multiple human trials show pharmacodynamic and clinical signals (esp. prostate/bladder).

Mechanisms: Sulforaphane (SFN) modifies Keap1 cysteines, stabilizing NRF2 and inducing HO-1, NQO1, GCLC, and phase II enzymes; it also inhibits class I/II HDACs and DNMTs, restoring p21 and other suppressors. SFN reduces CSC self-renewal (ALDH+/CD44+↓), impairs EMT, and sensitizes tumors to chemo/radiation. Clinical studies show PSA kinetics and tissue HDAC suppression in prostate, and reduced bladder cancer recurrence signals with broccoli sprout extracts.

Note: Generally safe from food sprouts; concentrated supplements may cause GI upset. Ensure active myrosinase (fresh sprouts or myrosinase-containing products) to generate SFN from glucoraphanin. Use caution with significant iodine deficiency/thyroid disease; avoid mega-doses around the time of certain TKIs without supervision. Synergies: <ul><strong>Cisplatin (Rx):</strong> Enhanced efficacy in bladder cancer.<li><strong>Curcumin (Natural):</strong> Boosts NRF2/HDAC inhibition in prostate models.</li><strong>Resveratrol (Natural):</strong> Synergizes for CSC targeting in breast cancer.</li><strong>Quercetin (Natural):</strong> Amplifies DNMT effects in colorectal cancer.</li></ul> Safety: Mild heartburn; monitor thyroid function.

Key Takeaway: Lead quinone from black seed with broad preclinical anticancer activity: pro-oxidant pressure in tumor cells, suppression of NF-κB/STAT3/PI3K-Akt, anti-angiogenesis, and apoptosis induction; shows chemo/radiosensitization in models but lacks robust oncology trials.

Mechanisms: TQ raises intracellular ROS in cancer cells while supporting antioxidant defenses in normal tissue; it inhibits NF-κB/STAT3 and PI3K-Akt, downregulates MMP-2/9 and VEGF, and activates p53/caspases with mitochondrial depolarization. TQ modulates drug transporters/CYPs and can sensitize tumors to cisplatin, doxorubicin, 5-FU, and radiation in vivo, reducing resistance pathways.

Note: Generally well tolerated at dietary intakes; clinical anticancer efficacy unproven. Bioavailability is modest—liposomal/nanoparticle formulations are under study. Potential interactions via P-gp/CYP; coordinate with oncology team if used with chemotherapy. Synergies: <ul><li><strong>Cisplatin (Rx):</strong> Enhanced efficacy in ovarian cancer models.</li><li><strong>Doxorubicin (Rx):</strong> Boosts cardiotoxicity reduction in breast cancer.</li><li><strong>Curcumin (Natural):</strong> Additive NF-κB inhibition in colorectal cancer.</li><li><strong>Resveratrol (Natural):</strong> Synergizes for apoptosis in prostate models.</li></ul> Safety: Hepatotoxicity at high doses; monitor LFTs; avoid in pregnancy.

Key Takeaway: PSK/PSP polysaccharides from Trametes versicolor activate innate/adaptive immunity (DCs, NK/CTL) and have improved survival signals in GI cancers as an adjunct to 5-FU–based therapy.

Mechanisms: β-Glucans engage Dectin-1/CR3 → Syk/NF-κB, maturing DCs and promoting Th1 cytokines (IL-12/IFN-γ). This enhances NK and CD8⁺ cytotoxicity and supports antigen presentation. Clinical trials/meta-analyses in gastric/colorectal cancers report OS benefits with PSK adjunct to chemotherapy.

Note: Generally well tolerated; mild GI upset possible. Use standardized extracts; products are not interchangeable. Coordinate with immunotherapy to avoid unintended cytokine overlap. Synergies: <ul><li><strong>5-FU (Rx):</strong> OS prolongation in gastric/colorectal cancer.</li><li><strong>Curcumin (Natural):</strong> Boosts DC maturation in lung models.</li><li><strong>Resveratrol (Natural):</strong> Synergizes for NK enhancement in breast cancer.</li><li><strong>Quercetin (Natural):</strong> Amplifies Th1 cytokines in prostate models.</li></ul> Safety: Rare hypersensitivity; monitor LFTs in long-term use.

Key Takeaway: Anthraquinones (emodin, rhein) intercalate DNA and inhibit Topo II, provoking DNA damage and apoptosis in models; also exerts laxative effects useful for cycle-based dosing. Human anticancer efficacy remains preliminary.

Mechanisms: Emodin/rhein insert between DNA base pairs and inhibit topoisomerase II, stabilizing cleavage complexes → DSBs and apoptosis (caspase activation, G2/M arrest). Additional effects include ROS modulation and NF-κB/PI3K-Akt downshift. As anthraquinone laxatives, they increase intestinal secretion and motility.

Note: Use cyclically due to cathartic effects; monitor hydration/electrolytes. Potential CYP/transport interactions; avoid with severe diarrhea or bowel inflammation. Synergies: <ul><li><strong>Doxorubicin (Rx):</strong> Enhanced Topo II poisoning in breast cancer models.</li><li><strong>Cisplatin (Rx):</strong> Boosts DNA damage in ovarian cancer.</li><li><strong>Curcumin (Natural):</strong> Additive NF-κB inhibition in colorectal models.</li><li><strong>Resveratrol (Natural):</strong> Synergizes for apoptosis in pancreatic cancer.</li></ul> Safety: Electrolyte imbalance risk; short-term use only.

Key Takeaway: Pharmacologic ascorbate (≥15–50 g IV) reaches millimolar plasma levels that generate extracellular H₂O₂, creating tumor-biased oxidative stress and DNA damage, while also acting as a TET cofactor to favor demethylation. Early human trials show feasibility, symptom relief, and signals of synergy with chemotherapy/radiation in select cancers.

Mechanisms: Tumor-selective H₂O₂ formation exploits relatively low catalase/peroxidase buffering in cancer cells → oxidative DNA lesions, ATP depletion, and apoptosis/necrosis. Ascorbate supports α-KG–dependent dioxygenases (e.g., TETs), promoting demethylation and differentiation programs. Additional data suggest immune modulation and anti-angiogenic effects, plus chemo-/radiosensitization via redox cycling.

Note: IV route required for pharmacologic levels; screen for G6PD deficiency; monitor glucose (POC meters can be confounded). Coordinate timing with redox-active chemotherapies and radiation. Synergies: <ul><li><strong>Gemcitabine (Rx):</strong> Improved efficacy in pancreatic cancer.</li><li><strong>Cisplatin (Rx):</strong> Boosts ROS in ovarian models.</li><li><strong>Curcumin (Natural):</strong> Amplifies H₂O₂ in colorectal cancer.</li><li><strong>Resveratrol (Natural):</strong> Synergizes for demethylation in breast cancer.</li></ul> Safety: Rare hemolysis in G6PD low; vein irritation with rapid infusion.

Key Takeaway: Calcitriol signaling (VDR) promotes differentiation and antiproliferative programs, while γ-tocopherol traps reactive nitrogen species and modulates lipid signaling; together they dampen NF-κB inflammation and enhance apoptosis/autophagy with emerging clinical support.

Mechanisms: Vitamin D ligates VDR → p21/p27 induction, cell-cycle arrest, differentiation, and immunomodulation; it also curbs pro-inflammatory cytokines. γ-Tocopherol preferentially scavenges peroxynitrite/RNS, modulates sphingolipid signaling, and contributes to cell-cycle arrest/apoptosis. Combination regimens show additive/synergistic anti-proliferative effects in several tumor models and early human studies.

Note: Prefer combined use; monitor 25(OH)D aiming for repletion (e.g., 30–50 ng/mL). Avoid excess calcium; consider magnesium sufficiency. γ-Tocopherol may outperform α-tocopherol for RNS scavenging. Synergies: <ul><li><strong>Doxorubicin (Rx):</strong> Potentiates anticancer activity in breast cancer cells.</li><li><strong>Curcumin (Natural):</strong> Enhances anti-inflammatory and antioxidant effects in prostate cancer.</li><li><strong>Resveratrol (Natural):</strong> Boosts apoptosis and cell cycle arrest in colorectal cancer.</li><li><strong>Quercetin (Natural):</strong> Synergizes to increase apoptosis in breast cancer.</li></ul> Safety: Hypercalcemia risk; monitor serum Ca and PTH.

Key Takeaway: D₃ supports VDR-driven differentiation and immune tone while increasing calcium absorption; K₂ activates matrix Gla protein (MGP) and osteocalcin to prevent ectopic calcification and favor skeletal deposition. Together they improve calcium routing and may add antiproliferative/autophagic pressure in some tumors.

Mechanisms: D₃ (cholecalciferol → calcitriol) activates VDR to induce cell-cycle arrest, apoptosis, and immune modulation. K₂ (MK-7/MK-4) provides γ-carboxylation of MGP/osteocalcin, reducing vascular/soft-tissue calcification and supporting bone health; K₂ also induces autophagy/apoptosis in tumor models and may suppress metastasis.

Note: Co-supplement to reduce D-alone calcification risk; monitor 25(OH)D and consider dietary calcium/magnesium balance. K antagonized by warfarin—avoid unsupervised combination. Synergies: <ul><li><strong>Magnesium (Natural):</strong> Enhances immune support in HER2-positive breast cancer.</li><li><strong>Ketogenic Diet:</strong> Boosts immunotherapy and metabolic stress on cancer cells.</li><li><strong>Curcumin (Natural):</strong> Increases apoptosis in prostate cancer.</li><li><strong>Resveratrol (Natural):</strong> Synergizes for VDR activation in colorectal cancer.</li></ul> Safety: Hypercalcemia risk; monitor serum Ca, PTH, and vitamin D levels.

Key Takeaway: Polyphenol-rich green walnut hull (notably the quinone juglone) suppresses pro-inflammatory NF-κB signaling, halts the cell cycle, and triggers intrinsic apoptosis; it also limits migration/invasion and provides antioxidant capacity in normal tissue. Anticancer evidence is preclinical across GI, breast, prostate, and bone models.

Mechanisms: Juglone and co-polyphenols downshift NF-κB/STAT3 and PI3K-AKT signaling, increase ROS stress within tumor cells, and prime mitochondrial apoptosis (Bax/Bcl-2 shift, caspases). Additional actions include G0/G1 or G2/M arrest via CDK modulation and reduced MMP-2/9 activity/EMT traits limiting invasion. Antioxidant effects are context-dependent (protective in normal cells, pro-oxidant tipping in tumors).

Note: Use standardized extracts; topical juglone can irritate skin. High-tannin preparations may upset GI or bind minerals (separate from iron/meds). Human efficacy trials are lacking—treat as experimental/adjunct only. Synergies: <ul><li><strong>Doxorubicin (Rx):</strong> Boosts cytotoxicity in breast cancer.</li><li><strong>Curcumin (Natural):</strong> Complements antioxidant effects in colon cancer.</li><li><strong>Resveratrol (Natural):</strong> Synergizes in reducing inflammation and tumor growth.</li><li><strong>Quercetin (Natural):</strong> Amplifies anti-proliferative in prostate models.</li></ul> Safety: GI upset at high doses; monitor mineral status.