A ketogenic diet starves the cancer cells of the nutrient energy they so heavily rely on for survival by inhibiting glycolysis and glutamine metabolism (glutaminolysis). The preclinical and emerging clinical evidence have been remarkably consistent regarding effects on cancer growth by this diet. In mice administered a ketogenic diet and in human-cancer case reports in which the ketogenic diet has been implemented, tumor growth rates have slowed. Preclinical animal studies have shown that a ketogenic diet induces significant metabolic stress in cancer cells. This stress can be exacerbated by administration of ketones which further inhibit tumor growth and metastasis. This oxidative stress is believed to render cancer cells and cancer stem cells more susceptible to both conventional and orthomolecular metabolic therapies. Emerging data supports that observation and encourages the exploration and development of new protocols for cancer treatment that utilize a ketogenic diet and ketone metabolic therapy as key component(s) of therapy.
Ivermectin is a highly safe antiparasitic drug with anti-proliferative effects on cancer cells in vitro via multiple intracellular signaling pathways. It promotes apoptosis (programmed cell death) and autophagy (self-digestion) of cancer cells, has a selective pro-oxidant effect on cancer cells, and upregulates expression of the p53 tumor suppressor gene. Importantly, there is evidence it targets and kills cancer stem cells, which does not occur with conventional and targeted chemotherapy, hormonal therapy, or radiation therapy. Published clinical evidence of its effectiveness in cancer treatment is limited to a few case series; however, anecdotal evidence of its efficacy in cancer treatment is growing based on reports from physicians throughout the world prescribing it, often in combination with benzimidazoles and a ketogenic diet.
Benzimidazoles: Fenbendazole and mebendazole are structurally similar antiparasitic drugs with anti-cancer effects. Specifically, they inhibit cancer cell division (microtubule polymerization), induce cancer cell apoptosis, and block both glucose fermentation and glutamine metabolism within cancer cells and cancer stem cells. Benzimidazoles also inhibit angiogenesis (new blood vessel development) within tumors. Mebendazole, unlike fenbendazole, crosses the blood-brain barrier so has potential therapeutic benefit for brain-cancer patients. Mebendazole also sensitizes cancer cells to conventional chemotherapy.
Although only mebendazole is approved for use in humans, the off-label use of it and fenbendazole, often in combination with ivermectin, are increasingly being explored with encouraging results in the treatment of multiple tumor types, particularly when used in conjunction with a ketogenic diet. There is published clinical evidence for effectiveness of mebendazole in multiple cancers and growing anecdotal evidence for efficacy of the benzimidazoles based on unpublished case reports from prescribing physicians.
Metformin, commonly used to treat non-insulin dependent diabetes, inhibits cancer cell and cancer stem cell proliferation both directly and indirectly through its glucose-lowering and anti-inflammatory activities. It also increases metabolic stress in cancer cells by inhibition of mitochondrial ATP production via the Krebs cycle and suppression of intracellular synthesis of glucose. In controlled clinical studies of diabetics treated with metformin, cancer incidence and mortality were reduced, and cancer cell responsiveness to chemo- and radiotherapy were improved.
Statins, specifically atorvastatin and simvastatin, developed for treatment of lipid disorders have also been shown in experimental studies to have multiple direct anti-cancer effects. These statins perturb energy metabolism of cancer cells by reducing cell surface expression of receptors responsible for glucose uptake. These statins also inhibit cancer cell growth, invasion, and metastasis; induce cancer cell apoptosis; and have anti-angiogenic activities. Their anti-cancer effects are likely, in part, pharmacologically mediated via inhibition of cholesterol synthesis, essential for growth and development of rapidly dividing tumors. Encouraging data has emerged from clinical studies where cancer-related mortality and/or all-cause mortality were reduced in multiple cancer types for patients treated with statins for dyslipidemias relative to patients not treated with statins.
Propranolol, a beta-blocker commonly prescribed for hypertension, has been shown experimentally to inhibit glucose fermentation in cancer cells by down-regulation of hexokinase 2 (HK2), and to reduce proliferation and promote apoptosis of cancer cells. It also inhibits metastasis and local invasion, effects mediated, in part, by over-expression of beta-adrenergic receptors in cancer cells. Propranolol has also been shown to inhibit tumor angiogenesis via inhibition of vascular endothelial growth factor (VEGF). By blocking activation of the sympathetic nervous system, propranolol inhibited stress-induced tumor growth in a mouse model of acute lymphoblastic leukemia.
Doxycycline inhibits the small mitochondrial ribosome (28S) due to structural homology with bacterial ribosomes, impairing mitochondrial protein synthesis and OXPHOS-dependent mitochondrial biogenesis—a metabolic vulnerability that is particularly exploitable in cancer stem cells (CSCs), which rely heavily on oxidative phosphorylation rather than glycolysis for ATP production and survival. Because CSCs exhibit elevated mitochondrial activity and depend on mitochondrial fitness for persistence, therapy resistance, and relapse, doxycycline effectively targets this specific cell population while sparing more differentiated cells, as demonstrated in clinical pilot studies showing reduced CSC populations in early breast cancer patients and preclinical models demonstrating delayed tumor relapse following chemotherapy. The therapeutic advantage lies in repurposing what was originally considered an antibiotic side effect into a relatively non-toxic strategy that selectively attacks the metabolic Achilles’ heel of treatment-resistant CSC populations, with ongoing development of modified derivatives further optimizing this mitochondrial-targeted approach for cancer therapy.
-Sources: PNAS, Nature, Frontiers in Oncology, & Marik’s Cancer & Metabolic Healing (Substack).
Vitamin D has both direct and indirect anti-cancer activities based on experimental evidence. It improves mitochondrial respiration (oxidative phosphorylation) and inhibits glycolysis and glutaminolysis pathways essential for energy production and survival of cancer cells. Vitamin D also directly induces differentiation and apoptosis and decreases proliferation and metastatic potential of cancer cells, and inhibits cancer stem cells and angiogenesis. Vitamin D’s indirect anti-cancer effects involve activation of the innate immune system (macrophages, natural killer (NK) cells, and neutrophils), which adversely affects the tumor microenvironment. Recent clinical data suggest the majority of cancer patients are Vitamin D deficient (< 20 ng/ml). Once study reported that patients with serum levels below 20 ng/ml were at a 30-50% increased risk for breast, prostate, and colon cancer. The blood levels of 25-hydroxy Vitamin D considered optimal for cancer prevention and treatment are ≥50 and 80 ng/ml, respectively (see references).
Vitamin C has demonstrated both experimental and clinical evidence of cytotoxicity to cancer cells at high concentrations or doses. Similar to Vitamin D, it inhibits glycolysis and reduces glutamate production via inhibition of glutamine synthetase, thereby decreasing energy production and increasing oxidative stress to cancer cells. Vitamin C also perturbs glucose metabolism directly by competing with glucose for entry into cellular mitochondria via glucose receptors. In vitro, it can induce apoptosis and inhibit proliferation and metastasis in drug-resistant cancer cells. High intravenous doses of Vitamin C have been shown to kill cancer cells while sparing normal cells. Although clinical trial outcomes are mixed on the efficacy of intravenous Vitamin C in cancer therapy, there is evidence from case studies of tumor regression with high intravenous dosing.
Curcumin has been shown to have numerous anti-tumor effects by its perturbation of multiple cellular signaling pathways in cancer cells. It down regulates HK-2, the key enzyme in glucose fermentation of cancer cells, and dissociates HK-2 from mitochondria which induces apoptosis (programmed cell death). Apoptosis of cancer cells is also induced by curcumin via several other critical cell signaling pathways. Important additional anti-cancer effects of curcumin include: cell cycle disruption; inhibition of proliferation, invasion, and metastasis; and suppression of angiogenesis in the tumor microenvironment. In experimental models, curcumin also demonstrated inhibitory effects on cancer stem cells.
The use of curcumin for the treatment of cancer has been limited due to its poor solubility, absorption, and bioavailability. The limited clinical studies that included curcumin as an adjunct to conventional chemotherapy have shown it to be well tolerated but demonstrated only small improvements in clinical outcomes when compared to chemotherapy alone. However, recent development of nanocarrier formulations of curcumin that improve its absorption and overall bioavailability could potentially lead to significantly improved therapeutic efficacy.
Melatonin has been shown in experimental models to have cytotoxic, anti-proliferative, and pro-apoptotic activities in cancer cells. These anti-cancer effects are believed to be caused, in part, by a melatonin-induced down-regulation of glycolysis (glucose fermentation) and switch to oxidative phosphorylation, the latter energy pathway being highly inefficient in cancer cells. Melatonin also suppresses angiogenesis and stimulates the innate immune system (T cells and NK cells) which further inhibit cancer growth. Meta-analysis of 21 randomized and controlled clinical trials where melatonin was given in combination with conventional chemo- and radio-therapy demonstrated improvements in partial and complete responses and stable disease after 1 year.
Green Tea is rich in flavonoids called green tea catechins (GTC). The most abundant and potent of these is epigallocatechin gallate (EGCG). At physiologically relevant concentrations, EGCG has demonstrated in vitro evidence of inhibition of mitochondrial glutamate dehydrogenase, a key enzyme involved in activation of glutamine metabolism. In addition, green tea extract has been shown to inhibit cancer stem cell proliferation in vitro by targeting mitochondrial metabolism and glycolysis. Collectively, these data provide evidence for potential benefits in treatment and prevention of cancers.
There is experimental evidence that GTCs demonstrate other anti-cancer effects: suppression of proliferation, invasion, and metastasis; inhibition of tumor-specific angiogenesis; and potent and selective induction of apoptosis. EGCG also inhibits cell signaling pathways that predispose to cancer-related deaths due to cachexia (wasting away). When used as sensitizing agents in conventional chemotherapy, GTCs potentiate the intended oncologic effects, reduce toxicity, and may allow for dose reduction of the chemotherapeutic agent. In a meta-analysis of 64 observational studies of tea drinkers, GTCs significantly reduced the risk of developing cancers of multiple organ and tissue types. In a well-designed randomized and controlled clinical study, the risk of developing prostate cancer was reduced from 30% to 3% in men with pre-existing pre-neoplastic lesions of the prostate when treated with 600 mg/day of GTCs for 1 year.
Sulforaphane suppresses the Warburg effect by reducing expression of central glycolytic enzymes—hexokinase II (HKII), pyruvate kinase M2 (PKM2), and lactate dehydrogenase A (LDHA)—in human prostate cancer cells (LNCaP, 22Rv1) and in transgenic mouse models (TRAMP and Hi-Myc), where neoplastic lesions demonstrated 32–45% reductions in these enzymes; simultaneously, in colon cancer cells (HCT116), sulforaphane inhibits hypoxia-induced HIF-1α protein accumulation and its downstream target VEGF, thereby suppressing migration and angiogenesis through the STAT3/HIF-1α/VEGF signaling axis, and though sulforaphane-mediated HIF-1α inhibition is expected to transcriptionally reduce HIF-1 target genes including GLUT1, HK2, and LDHA, direct measurements of these specific glycolytic genes downstream of HIF-1α suppression in colon and gastric cancer contexts are less documented in the literature compared to curcumin or resveratrol.
-Sources: Carcinogenesis (2019); International Journal of Oncology (2015), and Scientific Reports (2017).
Resveratrol targets aerobic glycolysis in cancer cells through three interconnected mechanisms: (1) direct inhibition of rate-limiting glycolytic enzymes—reducing expression and activity of HK2 (PMID: 25938543), PKM2 (PLOS One, 2012), PGK1 (Research Square/WJON), PFK (50% inhibition at 15 μM; PMID: 23454376), and LDH-A (Front. Pharmacol.)—to induce energy stress and apoptosis; (2) suppression of glucose uptake via the AKT/mTOR/GLUT1 axis, where resveratrol impairs GLUT1 membrane translocation without affecting total protein levels, selectively killing ovarian cancer cells while sparing normal cells (PMID: 25307508; Cancer Res. Abstract 1851); and (3) metabolic pathway modulation through ROS-dependent HIF-1α inhibition (PMID: 24221993) and CaMKKβ–AMPK activation, which shifts metabolism from glycolysis toward oxidative phosphorylation by activating pyruvate dehydrogenase (Saunier et al.; PMID: 29663499). These multi-target effects disrupt the Warburg effect, creating synthetic lethality in glycolysis-addicted cancers while limiting toxicity to normal tissues, positioning resveratrol as a promising metabolic disruptor pending improved bioavailability formulations.
Hyperbaric Oxygen Therapy (HBOT) has potent anti-cancer activity because a tissue environment of low oxygen (hypoxia) enhances malignant cells survival, angiogenesis, metastasis, glycolysis and glutaminolysis. The high oxygen environment induced by HBOT counteracts the tumor promoting effects of hypoxia and can target cancer stem cells and inhibit cancer growth and metastasis. HBOT is synergistic with a ketogenic diet in the suppression of cancer growth and metastasis with both of these interventions used with inhibitors of glycolysis and glutaminolysis in the Press-Pulse Therapy (see references).
Physical Activity is believed to have beneficial effects in cancer prevention by inhibiting weight gain and development of diabetes, both of which promote cancer stem cells and tumor development. Additionally, exercise decreases glycolysis and favors mitochondrial respiration via oxidative phosphorylation when conducted at low to moderate intensity. Physical activity also inhibits cancer cell proliferation and induces cancer cell death via apoptosis.
Cold therapy (cryotherapy), significantly enhances mitochondrial function through multiple mechanisms, leading to improved cellular energy production and metabolic health. This therapy stimulates mitochondrial biogenesis via the activation of transcription factors like PGC-1α, increasing the production of new mitochondria and enhancing the efficiency of existing ones to generate more ATP. Cold exposure also reduces oxidative stress by bolstering the antioxidant defense system, protecting mitochondria from damage. The activation of brown adipose tissue (BAT), rich in mitochondria, promotes non-shivering thermogenesis, further enhancing mitochondrial activity and improving glucose homeostasis and insulin sensitivity. This is particularly beneficial for individuals with impaired insulin function and even those with mildly elevated blood glucose levels, as it helps mitigate long-term organ damage. BAT activation also plays a crucial role in bone health and density, increases adiponectin levels (linked to longevity), and boosts irisin production, which improves insulin sensitivity, bone quality, and lean muscle mass. Additionally, cold exposure up-regulates FGF-21, a hormone associated with longevity and improved glucose metabolism. Under basal temperatures, HDAC3 primes UCP1 and the brown fat thermogenic program, ensuring acute cold survival through the activation of PGC-1α. Cold exposure also increases SIRT1 activity in skeletal muscle and BAT, enhancing thermogenesis, insulin sensitivity, and promoting the browning of white fat. Collectively, these effects make cold therapy a promising approach for optimizing mitochondrial function, enhancing metabolic health, and promoting longevity.
Sauna therapy, particularly infrared saunas, improves mitochondrial function through several key pathways. Exposure to high temperatures triggers the production of heat shock proteins, which protect and repair cellular structures, including mitochondria, by maintaining protein quality control. Additionally, sauna therapy stimulates mitochondrial biogenesis by activating PGC-1α, leading to an increase in the number of mitochondria. This therapy also enhances mitochondrial efficiency by optimizing the electron transport chain and oxidative phosphorylation processes, resulting in more ATP production per unit of substrate. Sauna use improves blood circulation and oxygen delivery, ensuring mitochondria have an adequate oxygen supply for efficient energy production. The detoxification benefits of sauna therapy, which eliminate toxins and heavy metals, reduce oxidative stress on mitochondria, allowing them to function more efficiently. Together, these effects contribute to improved cellular energy production and overall metabolic health, making sauna therapy a valuable tool for optimizing mitochondrial function.
The repurposed drugs, vitamins, and supplements briefly discussed here are currently being used by a growing number of oncologists and physicians in multi-faceted novel treatment protocols for metabolic cancer therapy. Our discussion of each is not intended as a recommendation or endorsement for their use but rather summaries of the supportive experimental and clinical evidence for their potential effectiveness in cancer therapy.
For comprehensive lists of drugs, vitamins, and supplements with strong, weak, or equivocal evidence of efficacy in cancer therapy and discussions of relevant dosing considerations, please see the second edition of Cancer Care (2024) by Dr. Paul E. Marik. This comprehensive and timely review of the relevant literature also provides current views on the potential of adjuvant therapies including Tumor Treating Fields (TTF), Photodynamic Therapy, and Hyperbaric Oxygen Therapy for cancer treatment.
Published dosing recommendations for several of the repurposed drug and vitamins presented are defined in: Baghli I, Makis W, Marik PE, Gonzalez MJ, Grant WB, Hunninghake R, Levy TE, Lim H, Cheng RZ, Bondarenko I, Bousquet P, Ortiz R, Mary M, D’Agostino, Martinez P. Targeting the mitochondrial-stem cell connection in cancer treatment: A hybrid orthomolecular protocol. J Orthomol Med 39(3): 1-15, 2024.
