Repurposed Drugs for Cancer (2023): What You Need to Know
A rapidly growing subcategory in the chemotherapeutic treatment of cancer is the utilization of prescription drugs originally approved for treating conditions other than cancer. Such off-label use of drugs has taken the world of integrative oncology by storm. This strategy has potential for increasing efficacy of treatment. At the same time, it raises deep questions on how we define naturopathic medicine, natural medicine, and our role as physicians. Will using pharmaceutical drugs to prolong a patient’s life fit into who we claim to be as naturopathic physicians?
One of the earliest non-cancer drugs noted to have anticancer side effect was cimetidine. Cimetidine was an early H-2 agonist approved for treating gastric ulcers in the late 1970s. Reports of an anticancer effect appeared not long afterward; the earliest was likely Armitage and Sidner’s 1979 paper,1 but Burtin’s 1988 trial usually receives the credit. Burtin reported that cimetidine or ranitidine combined with subcutaneous histamine improved survival of gastric cancer patients to the degree that patients survived six times longer than patients receiving palliative treatment alone.2 A double blind, placebo-controlled trial by Tonnesen, published the next year, showed that cimetidine alone at a normal dosage significantly prolonged survival in gastric cancer.3 Cimetidine is now reported helpful against a range of cancers, including renal, melanoma, gastric, and colorectal carcinomas.4 In Ali’s 2018 study, patients starting cimetidine after surgery for colorectal cancer delayed cancer recurrence.5
If cimetidine is the drug longest known for secondary usage in cancer, the best-known drug is likely metformin, the glucose-lowering agent that is first-line treatment for type-2 diabetes. Metformin decreases hepatic gluconeogenesis and improves insulin sensitivity. It was approved for treatment of type-2 diabetes in France in 1957, in the UK in 1958, Canada in 1972, and finally, in the US in 1994.6
One of the earliest non-cancer drugs noted to have anticancer side effect was cimetidine. Cimetidine was an early H-2 agonist approved for treating gastric ulcers in the late 1970s. Reports of an anticancer effect appeared not long afterward; the earliest was likely Armitage and Sidner’s 1979 paper,1 but Burtin’s 1988 trial usually receives the credit. Burtin reported that cimetidine or ranitidine combined with subcutaneous histamine improved survival of gastric cancer patients to the degree that patients survived six times longer than patients receiving palliative treatment alone.2 A double blind, placebo-controlled trial by Tonnesen, published the next year, showed that cimetidine alone at a normal dosage significantly prolonged survival in gastric cancer.3 Cimetidine is now reported helpful against a range of cancers, including renal, melanoma, gastric, and colorectal carcinomas.4 In Ali’s 2018 study, patients starting cimetidine after surgery for colorectal cancer delayed cancer recurrence.5
If cimetidine is the drug longest known for secondary usage in cancer, the best-known drug is likely metformin, the glucose-lowering agent that is first-line treatment for type-2 diabetes. Metformin decreases hepatic gluconeogenesis and improves insulin sensitivity. It was approved for treatment of type-2 diabetes in France in 1957, in the UK in 1958, Canada in 1972, and finally, in the US in 1994.6
During the early 2000s metformin also became the drug of choice for treating hyperinsulinemia and metabolic abnormalities associated with polycystic ovarian syndrome (PCOS). The first major report that associated metformin with lower cancer risk may have been Josie Evan’s 2005 study that examined medical records of over 300,000 people in Scotland. Just under 12,000 of these individuals had type-2 diabetes. Of these individuals, 923 were eventually diagnosed with malignant cancers. Those who had taken metformin had a significantly lower risk of being diagnosed with cancer [OR 0.79 (0.67 to 0.93)].7
Since then numerous papers have been published on metformin’s possible benefit in cancer. Observational studies, systematic reviews, and multiple meta-analyses of case-control and cohort studies suggest metformin use is associated with a 10-40% overall decrease in cancer incidence along with a similar decrease in mortality.6,8
Many of us were first exposed to the idea of using prescription drug cocktails to treat cancer by Ben Williams. Mr. Williams was diagnosed with glioblastoma in March 1995. He availed himself of a drug and supplement protocol that proved to be effective. He chronicled these treatment choices first on a website9 and in his 2002 book, Surviving Terminal Cancer: Clinical Trials, Drug Cocktails, and Other Treatments Your Oncologist Won’t Tell You About. The protocol he followed stood out not just because of the many nutritional supplements but also because he took multiple off-label drugs. When he first posted these protocols, I ignored the drugs, as they were not ‘naturopathic.’ I turn back to his list now with interest. What he did worked. Williams took a range of drugs including Accutane, Actos, and Celebrex that evidence suggested might have an additive or synergistic effect against glioblastoma. His list of supplements became the foundation that we have used with brain tumors.
Since then numerous papers have been published on metformin’s possible benefit in cancer. Observational studies, systematic reviews, and multiple meta-analyses of case-control and cohort studies suggest metformin use is associated with a 10-40% overall decrease in cancer incidence along with a similar decrease in mortality.6,8
Many of us were first exposed to the idea of using prescription drug cocktails to treat cancer by Ben Williams. Mr. Williams was diagnosed with glioblastoma in March 1995. He availed himself of a drug and supplement protocol that proved to be effective. He chronicled these treatment choices first on a website9 and in his 2002 book, Surviving Terminal Cancer: Clinical Trials, Drug Cocktails, and Other Treatments Your Oncologist Won’t Tell You About. The protocol he followed stood out not just because of the many nutritional supplements but also because he took multiple off-label drugs. When he first posted these protocols, I ignored the drugs, as they were not ‘naturopathic.’ I turn back to his list now with interest. What he did worked. Williams took a range of drugs including Accutane, Actos, and Celebrex that evidence suggested might have an additive or synergistic effect against glioblastoma. His list of supplements became the foundation that we have used with brain tumors.
The phrase ‘repurposing drugs’ first shows up in the medical literature in 2005 with two papers by D. W. Carley.10 In 2009, eight papers were published on the subject. These focused on the prohibitively high cost ($800 million) and long time (20-27 years) that it took to bring a new cancer drug to market and suggested that older, already approved drugs might have new uses and proposed ways to screen for anticancer action.11 In 2011, Vazquez-Martin suggested that metformin might be ‘repositioned’ to utilize its ability to target and eliminate cancer stem cells at preinvasive stages.12 Then in 2012, Michele Holmes and Wendy Chen at Harvard wrote their classic review: “Hiding in plain view: the potential for commonly used drugs to reduce breast cancer mortality.”
In this paper, they “… presented and evaluated the evidence for several commonly used over-the-counter and prescription medications—including aspirin (and other non-steroidal anti-inflammatory drugs), beta-blockers, angiotensin-converting enzyme inhibitors, statins, digoxin, and metformin, all of which have been evaluated among breast cancer survivors in prospective studies. Substantial scientific evidence supports the idea that some of these common and relatively safe drugs may reduce breast cancer mortality among those with the disease by an amount that rivals the mortality reduction gained by currently used therapies. In particular, the evidence is strongest for aspirin (approximately 50% reduction), statins (approximately 25% reduction), and metformin (approximately 50% reduction). As these drugs are generic and inexpensive, there is little incentive for the pharmaceutical industry to fund the randomized trials that would show their effectiveness definitively….Because of the multiple potential pathways that can be involved with cancer growth and metastases, tremendous interest remains in whether currently used non-cancer medications may potentially have anti-cancer effects.”13
This paper was the last calm before the storm; thereafter interest in repurposed drugs exploded. While this was an obscure idea in 2009, PubMed lists 247 citations for ‘repurposing drugs’ in 2017 and 312 for the following year. One might argue that this is due to a collective realization by researchers that this is an excellent idea. The excitement is in part due to a man in Belgium named Luc Verelst, whose sister was diagnosed with endometrial cancer in the summer of 2008. Like many of our patients, Verelst searched to find the best and most reliable treatments; and like them, he was overwhelmed, frustrated, and confused by the complex and contradictory information he found. In 2009, Mr. Verelst founded a non-profit organization called Reliable Cancer Therapies (RCT) to publicly share information on cancer treatments and to investigate new treatment options. He founded a second organization in 2013, the Anticancer Fund (ACF), with the ambitious goal of discovering a cure for cancer. As part of their mission, the ACF scientists took on the task of researching this concept of drug repurposing. They have cataloged potential repurposed drugs on a website (http://www.redo-project.org), produced summaries on many of these drugs, and are funding research on promising candidates.
Pan Pantziarka is the lead author on many of the papers produced by the “redo” scientists.14 Both Dr. Pantziarka’s first wife and son George had Li-Fraumeni Syndrome, a rare, autosomal dominant disorder linked to mutations in the p53 tumor suppressor gene that pre-disposes carriers to cancer; both died of cancer at young ages. Pantziarka is now the program director for drug repurposing at the Anticancer Fund and the coordinator of the Repurposing Drugs in Oncology (ReDO) project.
By February 2020, the ReDo-project database listed 310 drugs, sold for other uses, that might have potential efficacy in cancer care. Of these, half are supported by relevant human data and a fifth are supported by data from at least one positive clinical trial. The ReDO project is summed up in a 2018 paper by Pan Pantziarka et al. The full text is available online.15
Many patients find this entire concept exciting. But for us naturopaths, it is disturbing. There is no reason to assume using prescription drugs would be acceptable to my “drugless practitioner” naturopathic colleagues. Patients come to us because they want alternatives to taking drugs, in particular chemotherapy; even patients who have acquiesced to the oncological standards of care, still urgently want to avoid using further drugs. The business of repurposing pharmaceuticals seems to go against our profession’s underlying philosophy, and our patients will not hesitate to speak up to remind us.
The medical oncologists who work with our patients are usually unfamiliar with the concept of repurposed drugs and are rarely aware that there is research supporting such uses. A search on PubMed for “metformin AND cancer” (May 30, 2019) yielded 4,432 citations. Yet I cannot recall any medical oncologist ever suggesting to a patient that they take metformin because they have cancer.
Most of us were drawn to practice naturopathy by a deep trust in nature, though the word ‘trust’ does not do justice to our deep sense that nature can be relied on to heal the sick and injured. Perhaps faith would be a better word. Even as we talk about evidence-based medicine, we retain that faith in the Vis Medicatrix Naturae, We may have enrolled in naturopathic school to become nature doctors; but upon graduation, we became physicians, who specialize in naturopathy, but physicians, nevertheless. To quote Ryan Blum writing in the Journal of Ethics in 2009, “Physicians’ responsibilities to the patient are the same whether they utilize naturopathic, osteopathic, or allopathic diagnostics and treatments.”16 We may profess philosophical tenets about natural healing, but our obligation is to our patient’s best interest and some days that may be standard of care treatment. I have listened to patients profess our own naturopathic creed, “I believe that nature can heal all illness, that if we just discover the cause, I can cure my cancer naturally,” and I’ve been forced to admit an unwillingness to bet their survival on it.
By February 2020, the ReDo-project database listed 310 drugs, sold for other uses, that might have potential efficacy in cancer care. Of these, half are supported by relevant human data and a fifth are supported by data from at least one positive clinical trial. The ReDO project is summed up in a 2018 paper by Pan Pantziarka et al. The full text is available online.15
The medical oncologists who work with our patients are usually unfamiliar with the concept of repurposed drugs and are rarely aware that there is research supporting such uses. A search on PubMed for “metformin AND cancer” (May 30, 2019) yielded 4,432 citations. Yet I cannot recall any medical oncologist ever suggesting to a patient that they take metformin because they have cancer.
Most of us were drawn to practice naturopathy by a deep trust in nature, though the word ‘trust’ does not do justice to our deep sense that nature can be relied on to heal the sick and injured. Perhaps faith would be a better word. Even as we talk about evidence-based medicine, we retain that faith in the Vis Medicatrix Naturae, We may have enrolled in naturopathic school to become nature doctors; but upon graduation, we became physicians, who specialize in naturopathy, but physicians, nevertheless. To quote Ryan Blum writing in the Journal of Ethics in 2009, “Physicians’ responsibilities to the patient are the same whether they utilize naturopathic, osteopathic, or allopathic diagnostics and treatments.”16 We may profess philosophical tenets about natural healing, but our obligation is to our patient’s best interest and some days that may be standard of care treatment. I have listened to patients profess our own naturopathic creed, “I believe that nature can heal all illness, that if we just discover the cause, I can cure my cancer naturally,” and I’ve been forced to admit an unwillingness to bet their survival on it.
ASCO reported in October 2018 that 40% of the American public is certain that cancer can be cured naturally.17 Among our naturopathic patient population, probably double that number believe this. Sadly, this does not seem to be the reality. We find ourselves in the awkward situation of sharing with the patient what we know from experience, that spontaneous remissions triggered by natural therapies are rare and not dependable. Their best chance of survival is often a combination of natural therapies alongside the standard of care therapies offered by medical oncologists. And even then, positive outcomes are not certain. By adopting the title physician, we elevated ourselves into the modern era of evidence-based medicine and the responsibilities that come with believing in science, statistics, and peer reviewed publications.
The line patients draw between the pharmaceutical treatment of cancer using chemotherapy that sets it apart from the natural treatments is difficult to define. The simplest delineation is that materials that require a prescription are bad and that things sold in health food stores are good. My college chemistry teacher defined organic as “any chemical compound that contains a carbon atom.” That’s not how we use the term organic anymore. It is no easier to define what the “natural treatment of cancer” means. Many chemotherapy agents are naturally derived substances. Doxorubicin, the drug used to treat breast cancer, is derived from soil micro-organisms native to southern France. Taxol, used to treat breast and ovarian cancer, originated in the bark of the Pacific yew tree. Vincristine was derived from the periwinkle flower. You can’t find more natural treatments than these.
Patients will object that these natural chemo drugs have lost their true nature through chemical refinement, that during concentration or synthesis in an artificial process divorced from nature, their essence has been lost. If we tour the modern health food store and examine the shelves of natural supplements, only a scarce few meet this bar set for ‘natural’. Whether we are talking about amino acids, digestive enzymes, herbal extracts or vitamins, few still fulfill the old definition of natural being something one can cook up in their home kitchen.
This line between chemo and natural brings to mind that 1964 quotation from United States Supreme Court Justice Potter Stewart in Jacobellis v. Ohio. In attempting to define a threshold test for obscenity, Justice Stewart said, “I know it when I see it.”
Wade Boyle defined the difference between allopathic and naturopathic herbalism years ago in a way that might help (I paraphrase from distant memory): “The allopaths use herbs to control and suppress symptoms. Naturopaths use herbs to stimulate the patient’s Vital Force, to tonify organ systems and so to heal the patient.” A parallel distinction might apply to naturopathic cancer treatment.
The line patients draw between the pharmaceutical treatment of cancer using chemotherapy that sets it apart from the natural treatments is difficult to define. The simplest delineation is that materials that require a prescription are bad and that things sold in health food stores are good. My college chemistry teacher defined organic as “any chemical compound that contains a carbon atom.” That’s not how we use the term organic anymore. It is no easier to define what the “natural treatment of cancer” means. Many chemotherapy agents are naturally derived substances. Doxorubicin, the drug used to treat breast cancer, is derived from soil micro-organisms native to southern France. Taxol, used to treat breast and ovarian cancer, originated in the bark of the Pacific yew tree. Vincristine was derived from the periwinkle flower. You can’t find more natural treatments than these.
Patients will object that these natural chemo drugs have lost their true nature through chemical refinement, that during concentration or synthesis in an artificial process divorced from nature, their essence has been lost. If we tour the modern health food store and examine the shelves of natural supplements, only a scarce few meet this bar set for ‘natural’. Whether we are talking about amino acids, digestive enzymes, herbal extracts or vitamins, few still fulfill the old definition of natural being something one can cook up in their home kitchen.
This line between chemo and natural brings to mind that 1964 quotation from United States Supreme Court Justice Potter Stewart in Jacobellis v. Ohio. In attempting to define a threshold test for obscenity, Justice Stewart said, “I know it when I see it.”
We might say that allopathic physicians attempt to eradicate cancer cells while naturopathic physicians stimulate the body to fight the cancer. Every cancer patient comes to us hoping we will enlist their immune system to fight their cancer, what we might call the Holy Grail of Oncology. Yet tell a patient about the history of Coley’s toxins and how he isolated and cultivated bacteria from human excrement and used it via injection to stimulate an immune response and often as not, chemotherapy no longer sounds so bad to them. The new immunotherapy drugs, pembrolizumab is an example, that urge on the immune system to recognize cancer come with significant risks of provoking overreactions and creating autoimmune disease. Are these drugs natural in that they trigger a natural defense against cancer?
Patients come in seeing the world as black and white and wanting to choose one side over the other. So accustomed to modern political and social divisions, they expect a similar divide in our office and are drawn to online viewpoints that push for a similar medical dichotomy. Yet biology and medicine are more grey than black or white.
As physicians our obligation is to the patient’s well-being, and we must advocate for what will help them achieve both a longer and better life. We are obligated to use every tool at our disposal and enlist every resource available on behalf of our patients. To do less is to not act in their best interest. Otherwise we should stop calling ourselves physicians. I have lost my initial hesitancy about suggesting these repurposed drugs.
One approach I have found useful is to find already existing reasons for patients to take these drugs. For example, many cancer patients have type-2 diabetes. Yet few take metformin because treating diabetes has taken a backseat to treating their cancer. We check hemoglobin A1c status on all our cancer patients. The medical standard of care is to prescribe metformin for anyone with a 5.8% or higher A1c. Few patients or doctors follow these guidelines. If a patient’s results are in ‘metformin range’, it takes moments to find a study on PubMed reporting metformin’s benefit against their particular cancer.
If the patient has heartburn or gastric discomfort during chemotherapy, we explore the use of either cimetidine18 or a proton pump inhibitor such as omeprazole.19 While there is reason to be cautious about using PPIs with prostate cancer20 and with drugs that, like capecitabine, require stomach acid for absorption,21 in general PPIs relieve discomfort and bring a good argument that they may have anti-cancer action.
Patients come in seeing the world as black and white and wanting to choose one side over the other. So accustomed to modern political and social divisions, they expect a similar divide in our office and are drawn to online viewpoints that push for a similar medical dichotomy. Yet biology and medicine are more grey than black or white.
As physicians our obligation is to the patient’s well-being, and we must advocate for what will help them achieve both a longer and better life. We are obligated to use every tool at our disposal and enlist every resource available on behalf of our patients. To do less is to not act in their best interest. Otherwise we should stop calling ourselves physicians. I have lost my initial hesitancy about suggesting these repurposed drugs.
One approach I have found useful is to find already existing reasons for patients to take these drugs. For example, many cancer patients have type-2 diabetes. Yet few take metformin because treating diabetes has taken a backseat to treating their cancer. We check hemoglobin A1c status on all our cancer patients. The medical standard of care is to prescribe metformin for anyone with a 5.8% or higher A1c. Few patients or doctors follow these guidelines. If a patient’s results are in ‘metformin range’, it takes moments to find a study on PubMed reporting metformin’s benefit against their particular cancer.
If the patient has heartburn or gastric discomfort during chemotherapy, we explore the use of either cimetidine18 or a proton pump inhibitor such as omeprazole.19 While there is reason to be cautious about using PPIs with prostate cancer20 and with drugs that, like capecitabine, require stomach acid for absorption,21 in general PPIs relieve discomfort and bring a good argument that they may have anti-cancer action.
Most cancer patients during treatment are encouraged to keep a supply of antibiotics at home just in case. Not all antibiotics are equal when it comes to limiting cancer growth and I’ve taken to suggesting if they need to reach for one of these drugs that they try clarithromycin first.22
Many naturopathic patients have never let go of the idea that Candida overgrowth is the cause of all illness, including cancer; and with these people, it is easy to lobby for itraconazole.23 These same patients are often concerned about other types of parasites. Rather than just running an O&P, they could pretreat using mebendazole.24
If patients complain of inflammation after they are taking the anti-inflammatory supplements, like curcumin and Boswellia, they should consider diclofenac. Diclofenac is a potent inhibitor of COX-2 and prostaglandin E2 synthesis and has desirable effects on the immune system, the angiogenic cascade, chemo- and radio-sensitivity, and tumor metabolism.25
Patients with hypertension, especially those with ovarian cancer, should consider a betablocker like propranolol.26 A November 2018 study suggested betablockers positively affected ovarian cancer survival. Patients 60 or older who had taken betablockers for a year or more had a significantly better chance of outliving those not taking the betablockers. About half of the users were taking non-selective beta blockers (NSBB) while the rest were taking selective beta blockers (SBB). The NSBB acted faster, having a significant impact in about six months compared with two years for the SBB drugs to show effect. Risk of dying for those taking betablockers was about half of what it was for women not taking them.27
Artemisia has become popular and many patients are eager to be treated with it. They overlook the fact that the other antimalarial agents have stronger evidence in support and are cheaper and easier to take, in particular chloroquine or hydroxychloroquine.28
In the case of patients who display symptoms of cardiovascular disease, in particularly angina, they should protect themselves during chemo and radiation by taking nitroglycerine or a slow release nitrate.29 Then there are the PDE-5 inhibitors, angina drugs repurposed to treat erectile dysfunction, to consider.30 One can come up with creative arguments for their use.
There is another approach to using the ReDo database, which I call the Chinese menu approach. I grew up at a time when Chinese restaurants had fixed price meals but gave the diner options for different courses. One got to pick an appetizer from column A, a main dish from column B, a rice or noodle dish from column C and so on.
Although the Redo database lists drugs alphabetically, we can re-group them by action. For example, a number of different drugs listed increase nitric oxide. The list includes several antianginal drugs, including nitroglycerine,29 atenolol, bepridil, dalteparin, ranolazine, trimetazidine, and verapamil. As mentioned, the classic PDE5 inhibitors used to treat ED, including sildenafil, tadalafil and vardenafil are listed. Publications suggest a list of potential anticancer effects for these PDE5 inhibitors against a range of cancer cell lines using in vitro, and ex vivo xenograft animal models, including CLL,31 prostate,32 colorectal,33 gliosarcoma,34 breast,35 melanoma,36 multiple myeloma,37 lung,38 lymphoma,39 liver,40 head and neck,41 et cetera. There is human evidence suggesting benefit in treating Waldenstrom’s macroglobulinemia, penile squamous cell carcinoma, multiple myeloma, and to suppress MDSC numbers.
The recurrent theme here is that use of these PDE5 inhibitors potentiates or enhances the cytotoxicity of chemotherapy drugs. The same is true for the antianginal drugs. All increase blood flow and this action may be how they potentiate chemotherapy; they aid delivery of chemotherapy to poorly perfused tumors. During radiotherapy these drugs help oxygenate hypoxic tumor cells, so they become more responsive to radiation.
The lesson learned may be that we should proactively increase nitric oxide levels during active treatment and any one of these drugs might help. Translating this into naturopathic approaches might be to advocate for nutritional supplements that increase nitric oxide such as beet extracts or l-arginine. Think of vasodilation as our column A.
Metformin, of course, is on the list of repurposed drugs but so are other antidiabetic medications for type 2 disease, including canagliflozin, epalrestat (a reversible aldose reductase inhibitor used for the treatment of diabetic neuropathy), the sulfonylurea drugs glibenclamide and glipizide, the GLP-1 receptor agonist, liraglutide, pioglitazone, and repaglinide. These drugs display a range of mechanisms suggesting that their benefit may be due to lowering blood sugar, lowering insulin overproduction, or by increasing insulin sensitivity. Translating this might mean weight loss, exercise, or even berberine.
The Chinese restaurant approach would have us pick a vasodilator, then second, treat diabetes under column B. Scanning the ReDo list again, one might notice numerous antifungal medications, including clotrimazole, griseofulvin, itraconazole,23 ketoconazole, posaconazole, and tioconazole.
Itraconazole is the best documented of these drugs. Clinical trials have shown that patients with prostate, lung, and basal cell carcinoma have benefited from treatment with itraconazole, and there are additional reports of activity in leukemia, ovarian, breast, and pancreatic cancers. Focus on itraconazole has suggested a potential role as a potentiator for chemotherapeutic drugs, particularly as a possible agent to reverse multi-drug resistance (MDR) (though be cautious using it with rituximab in lymphoma42).
The benefit from these antifungals is probably the result of various mechanisms, including inhibition of multidrug resistance, inhibition of Hedgehog signaling43 and inhibition of angiogenesis44 rather than their basic action of reducing fungal populations. Yet as mentioned, many of our patients worry about fungal infections and this may inspire them to want to take these types of drug.
If Column C on the menu is itraconazole, we might want to include berberine not just because it acts like metformin but because berberine has a synergistic effect with itraconazole at killing yeast.45
There are several blood thinners on the list: anticoagulant drugs used post myocardial infarction or with heart arrythmias to reduce clotting, including aspirin, warfarin, bemiparin, clopidogrel, dalteparin, ticagrelor, tinzaparin and ticlopidine. A blood thinner might be our column D on the menu, even something as simple as fish oil.
While nothing prohibits naturopathic treatment that target each of our menu categories, we must remember the evidence supports the drugs rather than our substitutions. We may not be ready to actively encourage use of these drugs, but at the same time we should be careful not to discourage their use, especially if there are already clinical indications for our patients to take them for other conditions.
This is a work in progress. This is all so new that we hardly have more than anecdotal evidence to support the idea of using multiple repurposed drugs together at the same time, yet this is what many researchers now advocate.
1 . Armitage JO, Sidner RD. Antitumour effect of cimetidine. Lancet. 1979; 1(8121) 882–3.
24. Pantziarka P, et al. Repurposing Drugs in Oncology (ReDO)-mebendazole as an anti-cancer agent. Ecancermedicalscience. 2014 Jul 10;8:443. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4096024/pdf/can-8-443.pdf
Many naturopathic patients have never let go of the idea that Candida overgrowth is the cause of all illness, including cancer; and with these people, it is easy to lobby for itraconazole.23 These same patients are often concerned about other types of parasites. Rather than just running an O&P, they could pretreat using mebendazole.24
If patients complain of inflammation after they are taking the anti-inflammatory supplements, like curcumin and Boswellia, they should consider diclofenac. Diclofenac is a potent inhibitor of COX-2 and prostaglandin E2 synthesis and has desirable effects on the immune system, the angiogenic cascade, chemo- and radio-sensitivity, and tumor metabolism.25
Patients with hypertension, especially those with ovarian cancer, should consider a betablocker like propranolol.26 A November 2018 study suggested betablockers positively affected ovarian cancer survival. Patients 60 or older who had taken betablockers for a year or more had a significantly better chance of outliving those not taking the betablockers. About half of the users were taking non-selective beta blockers (NSBB) while the rest were taking selective beta blockers (SBB). The NSBB acted faster, having a significant impact in about six months compared with two years for the SBB drugs to show effect. Risk of dying for those taking betablockers was about half of what it was for women not taking them.27
Artemisia has become popular and many patients are eager to be treated with it. They overlook the fact that the other antimalarial agents have stronger evidence in support and are cheaper and easier to take, in particular chloroquine or hydroxychloroquine.28
In the case of patients who display symptoms of cardiovascular disease, in particularly angina, they should protect themselves during chemo and radiation by taking nitroglycerine or a slow release nitrate.29 Then there are the PDE-5 inhibitors, angina drugs repurposed to treat erectile dysfunction, to consider.30 One can come up with creative arguments for their use.
There is another approach to using the ReDo database, which I call the Chinese menu approach. I grew up at a time when Chinese restaurants had fixed price meals but gave the diner options for different courses. One got to pick an appetizer from column A, a main dish from column B, a rice or noodle dish from column C and so on.
Although the Redo database lists drugs alphabetically, we can re-group them by action. For example, a number of different drugs listed increase nitric oxide. The list includes several antianginal drugs, including nitroglycerine,29 atenolol, bepridil, dalteparin, ranolazine, trimetazidine, and verapamil. As mentioned, the classic PDE5 inhibitors used to treat ED, including sildenafil, tadalafil and vardenafil are listed. Publications suggest a list of potential anticancer effects for these PDE5 inhibitors against a range of cancer cell lines using in vitro, and ex vivo xenograft animal models, including CLL,31 prostate,32 colorectal,33 gliosarcoma,34 breast,35 melanoma,36 multiple myeloma,37 lung,38 lymphoma,39 liver,40 head and neck,41 et cetera. There is human evidence suggesting benefit in treating Waldenstrom’s macroglobulinemia, penile squamous cell carcinoma, multiple myeloma, and to suppress MDSC numbers.
The lesson learned may be that we should proactively increase nitric oxide levels during active treatment and any one of these drugs might help. Translating this into naturopathic approaches might be to advocate for nutritional supplements that increase nitric oxide such as beet extracts or l-arginine. Think of vasodilation as our column A.
Metformin, of course, is on the list of repurposed drugs but so are other antidiabetic medications for type 2 disease, including canagliflozin, epalrestat (a reversible aldose reductase inhibitor used for the treatment of diabetic neuropathy), the sulfonylurea drugs glibenclamide and glipizide, the GLP-1 receptor agonist, liraglutide, pioglitazone, and repaglinide. These drugs display a range of mechanisms suggesting that their benefit may be due to lowering blood sugar, lowering insulin overproduction, or by increasing insulin sensitivity. Translating this might mean weight loss, exercise, or even berberine.
The Chinese restaurant approach would have us pick a vasodilator, then second, treat diabetes under column B. Scanning the ReDo list again, one might notice numerous antifungal medications, including clotrimazole, griseofulvin, itraconazole,23 ketoconazole, posaconazole, and tioconazole.
Itraconazole is the best documented of these drugs. Clinical trials have shown that patients with prostate, lung, and basal cell carcinoma have benefited from treatment with itraconazole, and there are additional reports of activity in leukemia, ovarian, breast, and pancreatic cancers. Focus on itraconazole has suggested a potential role as a potentiator for chemotherapeutic drugs, particularly as a possible agent to reverse multi-drug resistance (MDR) (though be cautious using it with rituximab in lymphoma42).
The benefit from these antifungals is probably the result of various mechanisms, including inhibition of multidrug resistance, inhibition of Hedgehog signaling43 and inhibition of angiogenesis44 rather than their basic action of reducing fungal populations. Yet as mentioned, many of our patients worry about fungal infections and this may inspire them to want to take these types of drug.
If Column C on the menu is itraconazole, we might want to include berberine not just because it acts like metformin but because berberine has a synergistic effect with itraconazole at killing yeast.45
There are several blood thinners on the list: anticoagulant drugs used post myocardial infarction or with heart arrythmias to reduce clotting, including aspirin, warfarin, bemiparin, clopidogrel, dalteparin, ticagrelor, tinzaparin and ticlopidine. A blood thinner might be our column D on the menu, even something as simple as fish oil.
While nothing prohibits naturopathic treatment that target each of our menu categories, we must remember the evidence supports the drugs rather than our substitutions. We may not be ready to actively encourage use of these drugs, but at the same time we should be careful not to discourage their use, especially if there are already clinical indications for our patients to take them for other conditions.
This is a work in progress. This is all so new that we hardly have more than anecdotal evidence to support the idea of using multiple repurposed drugs together at the same time, yet this is what many researchers now advocate.
About the Author: Jacob Schor is a 1991 graduate of National College of Naturopathic Medicine in Portland, Oregon, and practiced in Denver, Colorado, until June 2019. He also has a BS degree in food science from Cornell University in Ithaca, New York. This earlier training in food chemistry and nutrition has influenced and informed his approach to naturopathic medicine throughout his career as a naturopathic doctor. He is a past president of the Colorado Association of Naturopathic Physicians and the Oncology Association of Naturopathic Physicians and also served on the board of directors of both associations as well as the American Association of Naturopathic Physicians. He is an associate editor for the Natural Medicine Journal and a regular contributor to the Townsend Letter.
References:
2 . Burtin C, et al. Clinical improvement in advanced cancer disease after treatment combining histamine and H2 histaminics (ranitidine or cimetidine). Eur J Cancer Clin Oncol. 1988;21:161–167.
3 . Tonnesen H, et al. Cimetidine treatment of stomach cancer. Ugeskr Læger. 1989;151:1549–1551.
4 . Siegers CP1, Andresen S, Keogh JP. Does cimetidine improve prospects for cancer patients?. A reappraisal of the evidence to date. Digestion. 1999 Sep-Oct;60(5):415-21.
5 . Ali AH, et al. The Effect of Perioperative Cimetidine Administration on Time to Colorectal Cancer Recurrence. Am J Ther. 2018 Jul/Aug;25(4):e405-e411.
6 . Heckman-Stoddard BM, et al. Repurposing metformin for the prevention of cancer and cancer recurrence. Diabetologia. 2017 Sep;60(9):1639-1647.
7 . Evans JM, et al. Metformin and reduced risk of cancer in diabetic patients. BMJ. 2005 Jun 4;330(7503):1304-5.
8 . Homburg R. Should patients with polycystic ovarian syndrome be treated with metformin? A note of cautious optimism. Hum Reprod. 2002 Apr;17(4):853-6.
9 . https://virtualtrials.com/williams.cfm
10. Carley DW. Drug repurposing: identify, develop and commercialize new uses for existing or abandoned drugs. Part I. IDrugs. 2005 Apr;8(4):306-9.
11. Tobinick EL. The value of drug repositioning in the current pharmaceutical market. Drug News Perspect. 2009 Mar;22(2):119-25.
12. Vazquez-Martin A, et al. Repositioning chloroquine and metformin to eliminate cancer stem cell traits in pre-malignant lesions. Drug Resist Update. 2011 Aug-Oct;14(4-5):212-23.
13. Holmes MD, Chen WY. Hiding in plain view: the potential for commonly used drugs to reduce breast cancer mortality. Breast Cancer Res. 2012 Dec 10;14(6):216.
14 . Pantziarka Pan, et al. (2018) ReDO_DB: the repurposing drugs in oncology database. ecancer 12 886
15. Pantziarka P, et al. The Repurposing Drugs in Oncology (ReDO) Project. Ecancermedicalscience. 2014 Jul 10;8:442.
16 . https://journalofethics.ama-assn.org/article/when-patient-and-physician-disagree-patientsbest-interest/2009-03
17 . https://www.asco.org/research-progress/reports-studies/national-cancer-opinion-survey
18. Pantziarka P, et al. Repurposing drugs in oncology (ReDO)-cimetidine as an anti-cancer agent. Ecancermedicalscience. 2014 Nov 26;8:485. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4268104/pdf/can-8-485.pdf
19. Zhang JL, et al. Effects of omeprazole in improving concurrent chemoradiotherapy efficacy in rectal cancer. World J Gastroenterol. 2017 Apr 14;23(14):2575-2584.
20. Gesmundo I, et al. Proton pump inhibitors promote the growth of androgen-sensitive prostate cancer cells through ErbB2, ERK1/2, PI3K/Akt, GSK-3β signaling and inhibition of cellular prostatic acid phosphatase. Cancer Lett. 2019 May 1;449:252-262.
21. Chu MP, et al. Association of Proton Pump Inhibitors and Capecitabine Efficacy in Advanced Gastroesophageal Cancer: Secondary Analysis of the TRIO-013/LOGiC Randomized Clinical Trial. JAMA Oncol. 2016 Oct 13.
22. Van Nuffel AM, et al. Repurposing Drugs in Oncology (ReDO)-clarithromycin as an anti-cancer agent. Ecancermedicalscience. 2015 Feb 24;9:513. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4341996/pdf/can-9-513.pdf
23. Pantziarka P, et al. Repurposing Drugs in Oncology (ReDO)-itraconazole as an anti-cancer agent. Ecancermedicalscience. 2015 Apr 15;9:521. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4406527/pdf/can-9-521.pdf24. Pantziarka P, et al. Repurposing Drugs in Oncology (ReDO)-mebendazole as an anti-cancer agent. Ecancermedicalscience. 2014 Jul 10;8:443. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4096024/pdf/can-8-443.pdf
25. Pantziarka P, et al. Repurposing Drugs in Oncology (ReDO)-diclofenac as an anti-cancer agent. Ecancermedicalscience. 2016 Jan 11;10:610. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4720497/pdf/can-10-610.pdf
26. Pantziarka P, et al. Repurposing Drugs in Oncology (ReDO)-Propranolol as an anti-cancer agent. Ecancermedicalscience. 2016 Oct 12;10:680. eCollection 2016. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5102691/pdf/can-10-680.pdf
27. Baek MH, et al. Impact of beta blockers on survival outcomes in ovarian cancer: a nationwide population-based cohort study. J Gynecol Oncol. 2018 Nov;29(6):e82.
28. Verbaanderd C, et al. Repurposing Drugs in Oncology (ReDO)-chloroquine and hydroxychloroquine as anti-cancer agents. Ecancermedicalscience. 2017 Nov 23;11:781. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5718030/
29. Sukhatme V, Bouche G, Meheus L, Sukhatme VP, Pantziarka P. Repurposing Drugs in Oncology (ReDO)-nitroglycerin as an anti-cancer agent. Ecancermedicalscience. 2015 Aug 27;9:568. https://www.ncbi.nlm.nih. gov/pmc/articles/PMC4583240/pdf/can-9-568.pdf
30. Pantziarka P, et al. Repurposing drugs in oncology (ReDO)-selective PDE5 inhibitors as anti-cancer agents. Ecancermedicalscience. 2018 Apr 11;12:824. doi: 10.3332/ecancer.2018.824.
31. Sarfati M, et al. Sildenafil and vardenafil, types 5 and 6 phosphodiesterase inhibitors, induce caspasedependent apoptosis of B-chronic lymphocytic leukemia cells. Blood. 2003;101(1):265–269.
32. Das A, et al. Sildenafil increases chemotherapeutic efficacy of doxorubicin in prostate cancer and ameliorates cardiac dysfunction. Proc Natl Acad Sci USA. 2010 Oct 19; 107
33. Serafini P, et al. Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function. J Exp Med. 2006 Nov 27; 203(12):2691-702.
34. Black KL, et al. PDE5 inhibitors enhance tumor permeability and efficacy of chemotherapy in a rat brain tumor model. Brain Res. 2008 Sep 16; 1230():290-302.
35 . Di X, et al. Influence of the phosphodiesterase-5 inhibitor, sildenafil, on sensitivity to chemotherapy in breast tumor cells. Breast Cancer Res Treat. 2010 Nov; 124(2):349-60.
36. Meyer C, et al. Chronic inflammation promotes myeloid-derived suppressor cell activation blocking antitumor immunity in transgenic mouse melanoma model. Proc Natl Acad Sci USA. 2011;108(41):17111–17116
37. Kumazoe M, et al. Phosphodiesterase 5 inhibitor acts as a potent agent sensitizing acute myeloid leukemia cells to 67-kDa laminin receptor-dependent apoptosis. FEBS Letters. 2013;587(18):3052–3057.
38. Li Q, Shu Y. Pharmacological modulation of cytotoxicity and cellular uptake of anti-cancer drugs by PDE5 inhibitors in lung cancer cells. Pharm Res. 2014;31(1):86–96.
39. Wang R, et al. Phosphodiesterase type 5 inhibitor Tadalafil increases Rituximab treatment efficacy in a mouse brain lymphoma model. J Neuro-Oncol. 2015;122(1):35–42.
40. Tavallai M, et al. Nexavar/Stivarga and viagra interact to kill tumor cells. J Cell Physiol. 2015 Sep; 230(9):2281-98.
41. Tuttle TR, et al. The cyclic GMP/protein kinase G pathway as a therapeutic target in head and neck squamous cell carcinoma. Cancer Lett. 2016 Jan 28; 370(2):279-85.
42 . Ringshausen I, et al. Antifungal therapy with itraconazole impairs the anti-lymphoma effects of rituximab by inhibiting recruitment of CD20 to cell surface lipid rafts. Cancer Res. 2010 Jun 1; 70(11):4292-6.
43. Kim J, et al. Itraconazole, a commonly used antifungal that inhibits Hedgehog pathway activity and cancer growth. Cancer Cell. 2010 Apr 13; 17(4):388-99.
44. Chong CR, et al. Inhibition of angiogenesis by the antifungal drug itraconazole. ACS Chem Biol. 2007 Apr 24; 2(4):263-70.
45. Luo H1, et al. In Vitro Susceptibility of Berberine Combined with Antifungal Agents Against the Yeast Form of Talaromyces marneffei. Mycopathologia. 2019 Apr;184(2):295-301.
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