Cancer Care: The Role of Repurposed Drugs and Metabolic Interventions in Treating Cancer by Dr Paul E. Marik was first published in August 2023. A second edition was released in October 2024 and is freely available at the Front Line COVID-19 Critical Care Alliance (FLCCC). A summary is also provided.
The author explicitly gives the usual disclaimer that the book is not to be used as a substitute for professional medical guidance. He also states that repurposing drugs is not new and he is not suggesting he has found a cure for cancer. The book is a “compendium” intended to inform people of treatments besides the “traditional orthodox approach”.
This reviewer has not read the first edition. The foreword indicates, amongst other things, that the second edition expands on the first as well as adding propranolol to the discussion.
The main text is 172 pages long, organized into 12 chapters. There are 3 appendices spanning 5 pages and references spanning 80 pages. There are 1,457 references.
There is obviously a lot of content. It is well-researched and cited, having enough specifics to support whatever point the author is trying to make. Although it is mostly accessible and not intended to be a basic biology textbook, it would be helpful to devote a short chapter covering some rudimentary biology, pharmacodynamics and pharmacokinetics.
Below are selected passages. This is not intended to be a summary. Please note that the paragraphs are not successive if there are breaks in between.
1. Introduction points out that cancer may not be due to the traditional explanation of mutation. The idea that cancer is a metabolic disease is not new. It was “first noted in 1927 by Otto Warburg who was awarded the Nobel Prize in Physiology or Medicine in 1931 for his discoveries”.
Curiously, it is not being overweight or obese that is most related to cancer; it is the presence of insulin resistance. (13)
Although the author is not necessarily against chemotherapy, there has been the lack of improvement over the years.
Based on data collected between 1992 and 1997 for the 22 most common malignancies, Morgan et al estimated the overall contribution of curative and adjuvant cytotoxic chemotherapy to 5-year survival in adults was estimated to be 2.3% in Australia and 2.1 % in the U.S. (17) More recent data from the U.S. indicate that the 5-year cancer survival rate has only increased from 63% to 68% over the last 25 years (1995 to 2018). Ladanie et al. showed that over the past 15 years, the improvement in overall survival by new cancer therapies is a meager 2.4 months. (18) The study by Del Paggio et al reports an improvement of 3.4 months over the last 30 years. (19)
There is considerable evidence that the genetic mutation theory may not be entirely correct. Dr. Thomas Seyfried provides a compelling argument that cancer is primarily a metabolic rather than a genetic disease. (29, 30) His underlying hypothesis is that cancer is a mitochondrial disorder with impaired oxidative phosphorylation and energy production; the genomic abnormalities are likely secondary to disordered energy production and cellular metabolism.
2. What Is Cancer: Understanding Its Pathogenetic Causes discusses cancer as a metabolic disease rather than DNA mutation.
Numerous studies show that tumor mitochondria are structurally and functionally abnormal and incapable of generating normal levels of energy. (32-37) In addition, there is compelling evidence that mitochondrial dysfunction, operating largely through the RTG response (mitochondrial stress signaling), underlies the mutator phenotype of tumor cells. (38-42) Impaired mitochondrial function can induce abnormalities in tumor suppressor genes and oncogenes.
Viruses have long been recognized as the cause of some cancers. It is interesting that several cancer-associated viruses localize to, or accumulate in, the mitochondria. Viral alteration of mitochondrial function could potentially disrupt energy metabolism, thus altering expression of tumor suppressor genes and oncogenes over time.
This chapter also discusses the possible mechanisms of observed “turbo cancer” even though there is much uncertainty.
The spike protein damages mitochondria and alters mitochondrial function; this may play a central role in cancer cell development and propagation. (80-83) SARS-CoV-2 results in dysregulated innate and adaptive immunity. Depletion of CD8+ and natural killer cells reduces immune surveillance and alters the tumor microenvironment to promote tumor proliferation and metastases. (84)
Jiang et al reported that spike protein localizes in the nucleus and inhibits DNA damage repair by impeding key DNA repair protein BRCA1 and 53BP1 recruitment to the damage site. (88) Spike protein impairs type I IFN signaling increasing the risk of cancer as type I IFN signaling suppresses proliferation of cancer cells by arresting the cell cycle, in part through upregulation of p53 and various cyclin-dependent kinase inhibitors. (89, 90)
This chapter also discusses cancer signal pathways and immunity.
The [cancer stem cell] CSC colony is slow-growing and resembles normal cells in many respects. Chemotherapy and radiation all attempt to kill the fast-dividing cancer cells; however, they also kill fastdividing normal cells, including the hair, lining of the gastrointestinal tract, and bone marrow. (13) However, like normal cells, chemotherapy spares CSC. Furthermore, both chemotherapy and radiation treatment have a stimulating effect on the CSC population, causing them to grow resistant new tumor cells and replace the bulk of what was removed (See Figure 1). (13, 225, 227)
Common repurposed drugs that can attack CSC include green tea extract, melatonin, vitamin D3, metformin, curcumin, statins (atorvastatin), berberine, mebendazole, doxycycline, ivermectin, resveratrol, aspirin, diclofenac phosphodiesterase 5-inhibitors, and omega-3 fatty acids. (13, 230-233)
As for chemotherapy, it can “stimulate more rapid cancer growth (proliferation)” and increase resistance to apoptosis, amongst other problems.
Another problem with chemotherapy is that the drugs make cancer more aggressive by activating massive inflammation in the body. Chemotherapy activates the inflammatory master controller, NF-ΚB, which produces the inflammatory cytokine IL-6. (234)
3. Preventing Cancer and 4: The Metabolic Approach to Treating Cancer discuss some commonsensical measures for preventing cancer. These include, amongst other things, quitting smoking, reducing alcohol consumption, taking vitamin D, omega-3 fatty acids, melatonin and getting adequate sleep.
If cancer is a metabolic disease, then the most effective treatments would be to “starve the cancer cell”. Although the mechanisms are not entirely clear,
almost all cancer cells are dependent on glucose as a metabolic fuel via aerobic glycolysis, (22, 23) with hyperglycemia being a potent promotor of tumor cell proliferation and associated with poor survival. (281)
The ketogenic diet is a high-fat, low-carbohydrate diet and has been demonstrated to be beneficial to patients with prostate cancer, breast cancer and lung cancer.
The Banting Diet, named after William Banting (1796–1878), is a low-carbohydrate diet of mainly animal protein and excludes all processed foods since the latter is also a major factor in health.
The EPIC Cohort study investigated the association between dietary intake according to amount of food processing and risk of cancer at 25 anatomical sites using data from the European Prospective Investigation into Cancer and Nutrition (EPIC) study. (316) In this study, in a multivariate model, substitution of 10% of processed foods with an equal amount of minimally processed foods was associated with reduced risk of overall cancer (hazard ratio 0·96, 95% CI 0·95-0·97), head and neck cancers (0·80, 0·75-0·85), oesophageal squamous cell carcinoma (0·57, 0·51-0·64), colon cancer (0·88, 0·85-0·92), rectal cancer (0·90, 0·85-0·94), hepatocellular carcinoma (0·77, 0·68-0·87), and postmenopausal breast cancer (0·93, 0·90-0·97).
Although intermittent fasting “may theoretically promote cancer cell proliferation”, this has not been observed.
The metabolic effects of intermittent fasting are numerous and include increasing insulin sensitivity, decreasing blood glucose levels, decreasing insulin levels, decreasing insulin-like growth factor, activating the sirtuin pathway, and activating autophagy.
As for insulin potentiation therapy, “such treatment may be hazardous (causing severe hypoglycemia) and is counterintuitive, as it may likely promote tumor cell proliferation.” There are only two published clinical trials assessing this method: one produced worse outcomes and the other does not provide patient-centered outcomes.
5. Metabolic and Lifestyle Interventions for Cancer Treatment further elaborates on the previous two chapters, focusing on reducing sugar intake, getting adequate quality sleep and getting adequate sunlight, amongst other things.
In Ayurvedic medicine (traditional medicine native to India), Ashwagandha has proven to be a safe and effective adaptogen. Randomized controlled trials (RCTs) have shown a significant benefit in terms of stress reduction, improved cognition and mood, and quality of sleep. (405-407) In a double-blind, placebo-controlled RCT, participants who had chronic stress were randomized to ashwagandha extract (300 mg twice daily) or placebo for 60 days. (408) At the end of 60 days, participants in the active treatment group had a 44% (p< 0.001) reduction in stress scores and a 28% (p< 0.001) reduction in cortisol levels. In a similar study, Ashwagandha resulted in a marked improvement in the quality of sleep in patients with insomnia. (409)
A large epidemiological study found women with higher solar UVB exposure had only half the incidence of breast cancer as those with lower solar exposure and that men with higher residential solar exposure had only half the incidence of fatal prostate cancer. (431)
Interestingly, whilst sunlight can cause relatively benign skin cancers, most skin cancer deaths are from melanoma which is due to a lack of sunlight.
Paradoxically, while sun exposure (UVb) increases the risk of non-melanoma skin cancer, sun exposure reduces the risk of melanoma and the overall risk of dying from cancer. (440, 442) In 1937, Peller and Stephenson reported that soldiers of the U.S. Navy, intensively exposed to open air, sun rays, and salt water, had eight-fold higher frequency of skin cancer and lip cancer, but the death rate among these cases of cancer was three-fold lower than expected. In addition, they reported a 44% lower incidence of other cancer-related deaths. (443) In patients with melanoma sun exposure is strongly negatively associated with death from melanoma. (444) An Italian study reported that sunbathing holidays after a diagnosis of melanoma were related to reduced rates of relapses (HR=0.3, 95% CI=0.1-0.9). (445) In the MISS study (Melanoma in Southern Sweden), there was a dose dependent increase in the risk of death with lower sun exposure, with a 40% higher risk of cancer-related death in the group with low sun exposure [sHR=1.4, 95% CI=1.04-1.6] as compared to those with greatest sun exposure. (442)
6. Repurposed Drugs contains the list of drugs discussed in the next four chapters corresponding to four “tiers”. It does include a sub-section that discusses the use of repurposed drugs in a peri-operative context. For example:
Beta-adrenergic signalling is implicated in the post-surgical metastatic process and numerous in vivo studies have reported that peri-operative propranolol is associated with a reduced rate of metastases. (462) … The combination of propranolol with a COX-2/PGE2 inhibitor, such as ketorolac or etodolac, has the potential to show synergism in a perioperative setting. (464, 465) Cimetidine has been studied in the post-operative period predominantly in patients undergoing colorectal surgery. (466) In a Cochrane meta-analysis of five studies (n=421) adjuvant cimetidine was associated with an improvement in overall survival (HR 0.53; 95% CI 0.32 to 0.87). (467)
It should be noted that cimetidine increases the plasma levels of propranolol, hence propranolol should be dosed carefully. (473)
The next four chapters discuss each drug, typically giving a description of what it is before discussing its anticancer pathways and mechanisms, clinical studies, benefits for specific cancers and dosage considerations. To avoid inflating the length of this article, passages are reproduced for a few selected drugs.
7: Tier One Repurposed Drugs – Strong Recommendation discusses 17 drugs.
• Vitamin D (as well as vitamin K)
Binding of vitamin D to its target, the vitamin D receptor, leads to transcriptional activation and repression of target genes and results in induction of differentiation and apoptosis, inhibition of CSCs, and decreased proliferation, angiogenesis, and metastatic potential. (576) Vitamin D induces apoptosis of cancer cells, (577) counteracts aberrant WNT-β catenin signaling, (578) and has broad anti-inflammatory effects via downregulation of nuclear factor-Κβ and inhibition of cyclooxygenase expression. (579)
• Propranolol
Wolter et al demonstrated that propranolol inhibited growth of a panel of 15 neuroblastoma cell lines and treatment induced apoptosis and decreased proliferation. Activity was dependent on inhibition of the β2, not β1, adrenergic receptor, and treatment resulted in activation of p53 and p73 signaling in vitro. (623) Furthermore, β-blockers increase the response to chemotherapy via direct antitumor and antiangiogenic mechanisms in neuroblastoma. (624) The most important function of propranolol acting via multiple mechanisms is to reduce metastatic spread. (625)
• Melatonin
• Metformin
• Curcumin
Curcumin has been shown to interfere with multiple cell signaling pathways in cancer cells (see Figure 10), including: (681-698) i. Cell cycle (cyclin D1 and cyclin E) ii. Apoptosis (activation of caspases and down-regulation of antiapoptotic gene products), proliferation (HER-2, EGFR, and AP-1) iii. Survival (PI3K/AKT pathway) iv. Invasion (MMP-9 and adhesion molecules) v. Angiogenesis (VEGF) vi. Metastasis (CXCR-4) vii. Inflammation (NF-kappa B, TNF, IL-6, IL-1, COX-2, and 5-LOX)
• Ivermectin
Ivermectin induces cancer cell apoptosis mainly through the mitochondrial pathway. (734) Chen et al demonstrated that ivermectin inhibited the viability and induced apoptosis of esophageal squamous cancer cells through a mitochondrial-dependent pathway. (744)
• Mebendazole/Fenbendazole/Albendazole
• Green tea
• Omega-3 fatty acids
Omega-3 FAs compete with linoleic acids (LA) as a key nutrient in cancer. The ratio of the two classes of FAs is important since omega-3 and omega-6 share the same biochemical pathways and can compete to generate imbalances. The precursor of the omega-6 FA, LA, is associated with pro-inflammatory response. Cancer progression seems to be influenced by the ratio omega-3/omega-6 FA in the diet, rather than by their singular intake. (790) While LA promotes the survival of tumor cells preventing their death, omega-3 FAs promote the self-destruction of the tumor cells, thus limiting the expansion of cancer.
• Berberine
• Atorvastatin or Simvastatin
Statins also reduce the number of cell surface GLUT-1 glucose receptors, thus reducing cancer cell activity by limiting the amount of energy available. Additionally, statins’ direct inhibition of HMGCR depletes the body’s stores of isoprenoids, which play a crucial role in controlling the growth and spread of cancer cells. (832)
• Phosphodiesterase 5 Inhibitors: Sildenafil, Tadalafil, and Vardenafil
• Disulfiram
• Ashwagandha
• Itraconazole
• Mistletoe
• Cimetidine
8: Tier Two Repurposed Drugs – Weak Recommendation discusses 8 drugs.
• Valproic Acid
VPA has anti-tumor activity by modulating multiple pathways including the induction of cell cycle arrest via the upregulation of cyclin-dependent protein kinase inhibitors; induction of Apo2 ligand or tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis, inhibition of Janus kinase/signal transducer and activator of transcription, phosphoinositide 3-kinase/Akt, and nuclear factor kappa B signaling pathways; and strengthening of tumor immunosurveillance. (954)
• Low Dose Naltrexone
• Doxycycline
• Spironolactone
Spironolactone’s primary mechanism of action in the therapy of cancer seems to be the regulation of DNA damage response. Spironolactone affects the hallmarks of immune protection, invasion, and metastasis activation, and cell death resistance. (1019)
Spironolactone can prevent cancer cells from repairing DNA damage by inducing the proteolytic degradation of the TFIIH complex’s (XPB) protein. (888, 1021-1024)
However, the negative effects of spironolactone's ability to reduce the incidence of cancer may be partially offset by its capacity to increase the death of CSCs and facilitate immune identification. (1022, 1024)
• Resveratrol
Resveratrol causes activation of the p53-dependent pathway. (1040) The inhibition of anti-apoptotic proteins of the Bcl-2 family, and activation of pro-apoptotic proteins such as Bad, Bak or Bax, by resveratrol has also been shown to be a mechanism for caspase activation and cytochrome c release. (1041) It has also been shown that resveratrol induces apoptosis via inhibiting the PI3K/Akt/mTOR pathway, modulating the mitogen-activated protein kinase pathway (MAPK) and inhibiting NF-ΚB activation. (550)
• Wheatgrass
• Captopril
• Clarithromycin
9: Tier Three Repurposed Drugs – Insufficient Data discusses 14 drugs.
• Cyclooxygenase inhibitors – Aspirin (ASA) and NSAIDs (Diclofenac)
• Nigella sativa
• Ganoderma Lucidum (Reishi) and other Medicinal Mushrooms
Antroquinonol, cordycepin, hispolon, lectin, krestin, polysaccharide, sulfated polysaccharide, lentinan, and Maitake D Fraction are the main anticancer compounds found in mushrooms. (1146) The therapeutic effects of these compounds include suppression of cancer cell growth, induction of autophagy and phagocytosis, improved immune system response, and induction of apoptotic cell death through upregulation of pro-apoptotic factors and downregulation of antiapoptotic genes. (1148) The expression of caspase-3, -8, and -9, AKT, p27, p53, BAX, BCL2, NFkB pathway, and mTOR (1149) were significantly implicated in these activities. (1148, 1150)
• Dipyridamole
• High-Dose Intravenous Vitamin C
• Dichloroacetate (DCA)
• Nitroglycerin
• Sulforaphane
• Artemisinin
• Cannabinoids
There is evidence from in vitro studies and animal models that cannabis and cannabinoids may have anti-tumoral activity that has not yet been convincingly translated into benefit in humans. (1248) Cannabinoids have direct tumor-killing effects by complexing with the CB1 receptor. This interaction leads to autophagy and increased apoptosis. In addition, cannabinoids have been demonstrated to inhibit vascular endothelial growth factor, thereby impairing angiogenesis, and decreasing tumor viability. In vitro studies also reveal that cannabinoids inhibit matrix mettaloproteinase-2, which allows cancer cells to become invasive and metastasize. Hence, preclinical evidence suggests that cannabinoids may inhibit tumor growth and proliferation by way of several mechanisms.
• Fenofibrate
• Niclosamide
• Pao Pereira
• Dandelion Extract
• Annona muricata (Soursop or Graviola)
10. Tier Four Repurposed Drugs – Recommend Against covers B Complex Vitamins and Antioxidants, colchicine, essiac and flor-essence, shark cartilage and laetrile (amygdalin). These substances are generally ineffective for cancer patients, even toxic.
11. Potential Adjunctive Therapies discusses four treatments: therapeutic hyperthermia, tumor treating fields, photodynamic therapy and hyperbaric oxygen therapy. Below is a passage regarding therapeutic hyperthermia since cancer cells suffer irreversible damage at 40°C to 43°C depending on dosage.
The biochemical processes affected by heat are several, as outlined by Pietrangeli and Mondovi and summarized below: (1381) • DNA, RNA synthesis, DNA repair mechanism and cell respiration are inhibited. • Tumor cell membranes in the presence of heat become more permeable and fluid. This may partially explain the increased uptake of drugs. • DNA polymerases-β key enzymes in multistep repair system and are strongly inhibited. • Mitochondria suffer structural alterations in their cristae • Enhanced production of heat shock proteins (HSP) affects thermo-tolerance and tumor immunogenicity. • Heat increases the influx of reactive oxygen radicals mediating cytotoxicity. • Hyperthermia is a potent inducer of cancer cell apoptosis. (1382) Hyperthermia in combination with drugs promotes synergistic cancer cell apoptosis.
12. Chemotherapy: A Basic Primer briefly discusses chemotherapy, which drugs can be plant-derived or of synthetic origin. There are multiple types in terms of mechanisms and clinical practice involves using in combination.
Chemotherapy agents in general act by killing rapidly dividing cells. Therefore, these agents act on the rapidly proliferating population of cancer cells. As the tumor increases in size the degree of cellular heterogeneity increases. The greater the degree of heterogeneity the less likely will be the response to chemotherapy.
Whilst it can be effective, it can obviously kill healthy cells as well.
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