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In 2009 Chen et al. reported that pretreatment of adenocarcinoma cells 12 to 24 hours before chemotherapy increased their sensitivity to treatment. Dosing the PPIs a full 24 hours ahead of chemo had the greatest impact at increasing tumor cell apoptosis.16
That same year, 2009, De Milito et al. reported on PPI treatment of mice implanted with various forms of human melanoma. PPI treatment reduced tumor growth, induced tumor cell death, and dramatically increased survival of the mice without noticeable toxicity.17
Over time, the explanations of the mechanism of action for PPI cancer destruction have grown in detail. In a 2010 paper, Fais suggests that because PPIs are prodrugs requiring acidity to be activated, they actually target the acidic tumor mass, which
… triggers a rapid cell death as a result of intracellular acidification, caspase activation and early accumulation of reactive oxygen species into tumour cells. As a whole, the devastating effect of PPIs on tumour cells suggest the triggering of a fatal cell toxification. Many human tumours, including melanoma, osteosarcoma, lymphomas and various adenocarcinomas are responsive to PPIs. This appears highly conceivable, in as much as almost all human tumours are acidic and express high levels of proton pumps. Paradoxically, metastatic tumours appear to be more responsive to PPIs being more acidic than the majority of primary tumours.18
In the last couple of years, we see acceleration in the number of publications reporting that PPIs have benefit against cancer.
In 2013 Huang reported that PPIs increased the sensitivity of gastric cancer cells to cisplatin, increasing apoptosis in the cancer cells but not in healthy surrounding tissue.19 In 2014 we begin to see reports on human clinical trials. Papagerakis et al. reported on head and neck squamous cell carcinoma patients (HNSCC). These patients are often given some form of antacid to control acid reflux. This study compared the effect of using histamine receptor-2 antagonists or proton pump inhibitors in a group of 596 HNSCC patients. Median follow-up was 55 months. Taking antacid medications was associated with significantly better overall survival times.20
Also in 2014, an in vitro study by Goh et al. of triple-negative breast cancer suggested potential benefit; Nexium (esomeprazole) increased the cytotoxicity of doxorubicin against TNBC cells in a dose dependent manner but had no effect on healthy breast cells.21
That same year, 2014, PPIs were reported to affect tumor cell survival, metastatic potential and chemosensitivity of esophageal cancer cell lines.22 In January 2015, Zhang reported that pantoprazole (Protonix) was useful in reversing doxorubicin resistance in gastric cancer cells and also reducing the aggressiveness of these cancer cells.23 Yu reported in October 2015 that "treatment with lansoprazole (Prevacid) and doxorubicin was more effective in delaying tumor growth as compared to either agent alone."24
Also in October 2015, Lee et al. reported that omeprazole enhanced the effects of paclitaxel in chemoresistant epithelial ovarian cancer.25 In April 2016 Canitano et al. reported that lansoprazole (Prevacid) is effective against multiple myeloma.26
These studies are popping up in the literature quickly now. It seems that a variety of PPIs have potential benefit against a wide range of cancers.
Back in early 2015, Zako et al. described another mechanism for why PPIs inhibit cancer. They reported that PPIs are effective inhibitors of the thioesterase activity of human fatty acid synthase (FASN). This is "… the enzyme responsible for de novo synthesis of free fatty acids, [and] is up-regulated in many cancers. FASN is essential for cancer cell survival and contributes to drug resistance and poor prognosis. However, it is not expressed in most nonlipogenic normal tissues. Thus, FASN is a desirable target for drug discovery."27 (Imagine what drug companies must think about this; here they are investing big bucks into creating drugs to knock out FASN only to find that a bunch of cheap OTC drugs are already available to do this.)
None of these PPI papers mention changing IGF-1 levels as a possible mechanism of action. Whether lowering IGF-1 levels will prove useful to understand the anticancer action of PPIs is still up in the air, though it looks less likely the more papers that are published. These PPI drugs are potentially useful in treating cancer because they do what they do best: they inhibit proton pumps and so prevent cancer cells from creating a comfortable microenvironment that allows them to flourish. Time will tell whether the IGF-1 effect garners further interest.
Time may also tell if this new understanding of the acidic tumor microenvironment will prove to be congruent with those older theories of tumor acidity and whether dietary interventions focused on alkaline ash foods actually provide benefit. As many of you are aware, scientific validation of these later ideas is scarce. High-alkaline diets may or may not change rate of bone loss in osteoporosis.28 A 2008 meta-analysis of 25 studies examining bone loss and dietary acidity did not reach firm conclusions. While the data suggested "… a linear association between changes in calcium excretion in response to experimental changes in net acid excretion," the authors added that this was "not evidence that the source of the excreted calcium is bone or that this calciuria contributes to the development of osteoporosis."29
Dwyer in 1985 suggested that urine pH did fluctuate with dietary alkalinity but stated that quantitative predictions were difficult.30 I have found no information suggesting that an alkaline diet shifts the pH of the tumor microenvironment the way that PPIs do.
A paper by veterinarians Walsh et al. published in September 2015 is worth reading. It describes using PPIs as adjunctive therapy in treating cancer in companion animals (both cats and dogs) and provides an excellent review of both history and theory of how PPIs target cancer cells.31
Reading this paper by Walsh et al. left me befuddled. They summarize the progression of discovery, testing, theory, and benefit in a straightforward manner as if everyone were well aware of these developments. They are wondering whether using PPIs will work as well in dogs and cats as it does in humans. They write as if using PPIs to treat human cancer is a well established strategy, a done deal.
We naturopaths who see a lot of cancer patients should be thinking of using these PPI drugs much more often, in particular in situations of chemoresistance.32
So why aren't we?
Sure, long-term use of PPIs comes with risk of gastritis, pneumonia, and vitamin deficiency but let's keep this in perspective. Long-term life with cancer also comes with risks. We need to keep our priorities straight. Attacking cancer should usually take priority. If we don't stop the cancer, worrying about developing B12 deficiency half a decade in the future seems inappropriate.
We haven't been talking about the benefit of PPIs much in our naturopathic circles. When we do talk about PPIs, it is only to say how bad they are. It was only by chance, by looking to justify taking omeprazole instead of fasting, that I came across these data.
As naturopathic practitioners, we are correct to emphasize natural approaches to treating disease. Yet as doctors and physicians, we are ethically bound to put the good interests of our patients foremost in our decision-making. In the case of PPIs, it seems that we have been so bound up in our worldview, we haven't noticed their potential to be beneficial in cancer treatment.
It is one thing to advocate for patients to choose natural alternatives when dealing with non-life-threatening health conditions. Cancer is different. We are ethically bound to lay all the choices on the table and help patients make informed decisions between them, balancing all factors. Neglecting to mention that inexpensive OTC PPIs might better their chances of survival would seem a serious omission, even if these drugs are pharmaceuticals.
Note: Aside from the basic cautions that we are well aware of regarding PPIs, there are two newer concerns about using them. First, a 2015 paper suggests concomitant administration of PPIs with capecitabine is associated with increased recurrence risk in early stage colorectal cancer.33
It was thought that PPIs interfere with the action of clopidogrel (Plavix). Omeprazole and esomeprazole in particular inhibit CYP2C19-mediated conversion of clopidogrel to its active metabolite and thus reduce clopidogrel's effect, so FDA labeling recommends avoiding these two PPIs when taking clopidogrel.34 Several studies have failed to demonstrate a problem. In a March 2015 study of 325,559 people taking both clopidogrel and a PPI, hazard ratios for ischemic stroke did not vary significantly between different PPIs; or in particular in comparison with pantoprazole, the PPI that does not interact with clopidogrel.35
Notes .pdf
Jacob Schor, ND, FABNO, has practiced as a naturopathic physician in Denver, Colorado, with his wife, Rena Bloom, ND, since they graduated from National College of Naturopathic Medicine in 1991. He was humbled in 2008 when presented with the Vis Award by the American Association of Naturopathic Physicians (AANP). He has had the honor of serving the members of the Oncology Association of Naturopathic Physicians as a board member and currently as president. Dr. Schor began a term on the AANP's board of directors in January 2012. He is a frequent contributor to, and associate editor of, the Natural Medicine Journal.
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