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I have crossed a line recently and started doing something in my practice that some may think disqualifies me as a naturopathic physician. I have begun encouraging some cancer patients to take proton pump inhibitors (PPIs). These are the drugs that stop acid production in the stomach. Drugs such as Prilosec (omeprazole), Prevacid (lansoprazole), Nexium (esomeprazole), or Protonix (pantoprazole).
It is not just my colleagues who consider this outrageous. You should see the reaction of some of my patients. The very idea is sacrilegious (though using such a term implies that the practice of naturopathic medicine is a religious endeavor, which I still assume it is not). Kosher vegans are generally more open to eating cheeseburgers than our patients are to taking these kinds of drugs.
Let me explain how I came to value proton pump inhibitors. It started back in 2008 when I began to suggest fasting before cancer chemotherapy. In an ideal world, a world of absolute perfect patient compliance, my patients would stop eating for half a week before each chemotherapy infusion. Then once their cancer treatments were completed, they would continue to fast for at monthly intervals for the rest of their long and happy lives.
This fasting before chemo strategy came from Valter Longo's report in Science.1 Longo had found that normal cells, but not cancer cells, grew slower when really hungry. This differential stress response to hunger provided a strategy to focus the effects of chemotherapy on killing cancer cells while reducing damage to healthy cells. After experimenting on various cancer cell lines, Longo tested his strategy on mice and "short-term starvation provided complete protection to mice but not to injected neuroblastoma cells against a high dose of the chemotherapy drug/pro-oxidant etoposide." In other words, really hungry mice were unaffected by chemotherapy, yet cancer cells in their bodies were still killed by chemo. This looked like a way to decrease the toxicity of chemo while still allowing it to do what we needed it to.
Our patients started "trying this at home" and quickly reported back that they felt better. Their reports matched the results that Longo would eventually publish in 2009 that the classic unpleasantness of chemotherapy, the fatigue, nausea, vomiting, decreased by 50% to 70% if patients fasted before their infusions.2-4
It became apparent over the years that patients didn't have to totally fast; they simply had to drop their caloric intake significantly. Longo started to track levels of insulinlike growth factor 1 (IGF-1) as a biomarker for fasting and reported that caloric restriction, simply dropping energy intake, was enough to lower IGF-1 and to reduce chemo side effects.
Over time we eased up on our patients, and instead of water fasts we suggested to patients to drop to a vegan 500 calorie/day diet for 3 days prior to chemo day; we measured IGF-1 levels regularly, hoping to see them drop levels by a third.
We were particularly encouraged by animal studies that suggest that caloric restriction in combination with chemotherapy significantly improves long-term survival in a range of cancer types. "Cycles of starvation were as effective as chemotherapeutic agents in delaying progression of different tumors and increased the effectiveness of these drugs against melanoma, glioma, and breast cancer cells."5
All of this sounds fantastic on paper, but have you ever tried to get patients to fast every 2 or 3 weeks? It's not easy. It's really hard to do. We do not live in an ideal world.
In the real world in which most of us practice, it is really hard to get cancer patients to fast or even restrict calories. Not only do they get hungry, but they also get no support from their oncologists, who often advise them against this strategy in rather strong terms, as in, "That will kill you."
Thus I was highly intrigued when a 2014 study by Maggio et al. suggested that there might be an alternative approach. Maggio reported that in a group of 938 older people, use of PPIs was associated with significant drops in IGF-1 levels. After all the statistical adjustments were made, non-PPI users had a mean IGF-1 level of 110 compared with 82 in PPI users.6 It struck me that it might be easier to get patients to swallow a daily dose of omeprazole than to fast.
Yet most of my patients have such a deep aversion to these PPI drugs, fasting may actually be an easier treatment to get them to try.
Proton pump inhibitors have several long-term consequences that most people have the good sense to want to avoid. I reviewed the downsides of PPIs in Naturopathy Digest back in 2007 and described a number of troublesome consequences that result from long-term use of these drugs. Taking PPIs triples risk of serious bowel infection. These drugs double the risk of pneumonia and triple the risk of hip fracture.7 They also increase risk of vitamin B12, iron, and calcium deficiency. There is a good reason for healthy people to avoid PPIs.
Back in 2007, we believed that the increase in hip fractures was because low stomach pH from the PPI prevented calcium absorption, leading to calcium deficiency and weaker bones. Now that we know the impact that these drugs have on IGF-1, a better explanation for the increased fractures is that the drop in IGF-1 slows bone building and leads to loss bone integrity.
My initial assumption is that using PPIs might be a trade-off. The hope was that the drugs' side effects would be outweighed by the reduction in chemo side effects. While taking PPIs long term is a clear problem, I hoped that just taking them for a week at a time it would be less risky.
Could PPIs have a direct action against cancer, I wondered? After all, an earlier class of antacids may have anticancer action. These drugs reached the market years ahead of PPIs and one of them in particular, cimetidine, has a long reputation of being used to treat cancer.
Cimetidine isn't a PPI; rather, it is an H2 receptor antagonist.8 This drug's reputation has swung back and forth over the years. In a 2012 Cochrane review Deva and Jameson reported results of a meta-analysis in which six studies published from 1995 to 2007 that included a total of 1229 patients were analyzed. Of these six trials, five used cimetidine as the experimental drug, while one used another H2 antagonist, ranitidine. When the data from these six trials were combined, there was a trend toward improved survival that did not reach statistical significance. When just the data from the five cimetidine trials (n = 421) were analyzed, there was a statistically significant improvement in overall survival (HR 0.53).9
It turns out that there are also data suggesting that PPIs have an anticancer action and offer benefit to cancer patients. These studies don't mention IGF-1. Apparently PPIs have a pronounced anticancer through other pathways and mechanisms
The earliest mention that I've come across is a 1996 Japanese paper that reported that PPIs significantly reduced pancreatic tumor growth in mice compared with controls (p < 0.05).10
A 1997 paper reported that breast cancer cells had a much greater capacity to acidify their extracellular microenvironment than healthy breast cells. "Metastatic breast cancer cells from pleural effusions were up to 200-fold more active in acidifying their extracellular milieu than non-malignant mammary cells cultured in the same conditions. …"11
PPIs by doing what they do best, inhibiting proton pumps, interfere with this acidification process that is important for cancer cell survival and growth.
In 2004, Luciani et al. reported that they had tested whether PPIs could inhibit the acidification of the tumor microenvironment and so increase the sensitivity of tumor cells to chemotherapy drugs. First they demonstrated that pretreating cancer cells, including melanoma, adenocarcinoma, and lymphoma cells, with PPIs in vitro "… sensitized tumor cell lines to the effects of cisplatin, 5-fluorouracil, and vinblastine, with an IC50 value reduction up to 2 logs." Then they "… evaluated human melanoma growth and cisplatin sensitivity with or without omeprazole pretreatment in mice implanted with human melanoma tumors. … Oral pretreatment with omeprazole was able to induce sensitivity of human solid tumors to cisplatin…" prompting the researchers to conclude that their "… results open new possibilities for the treatment of drug-resistant tumors through combination strategies based on the use of well-tolerated pH modulators such as PPIs."12
Several theories have been put forward to explain why blocking acidification of the tumor microenvironment is useful:
It is hypothesized that hypoxia and acidity may contribute to the progression from benign to malignant growth. In particular, the unfavorable environment may induce the selection of tumor cells able to survive in acidic and hypoxic conditions. In fact, the common components of the cancer phenotype result from active selection, and characteristics of tumor microenvironment may create the best condition for this selection. Acidity, in particular, has been shown to have a role in resistance to chemotherapy, proliferation and metastatic behavior. In fact, a mechanism of resistance to cytotoxic drugs may be the alteration of the tumor microenvironment through changes of the pH gradient between the extracellular environment and cell cytoplasm. The extracellular pH of solid tumors is significantly more acidic than that of normal tissues, thus impairing the uptake of weakly basic chemotherapeutic drugs and reducing their effect on tumors.
I have often explained to patients that the acidic state of tumors is the result of lactate generated by anaerobic metabolism, saying it is analogous to the lactic acid that causes muscle pain during anaerobic workouts at the gym. Apparently, this is not actually the truth; anaerobic respiration "… is not the major mechanism responsible for the development of an acidic environment within solid tumors." Actual pH control/homeostasis depends on a much more complex framework of chemical interactions that cancer cells appear to hijack in order to both protect themselves and to create an acidic environment that makes it difficult for normal cells to thrive. The cancer cells themselves are creating an acidic microenvironment for their own purposes.
The focus of the current PPI research is on the vacuolar-type (V-type) H(+)-ATPases, which pump protons across the plasma membrane; these may play the key role in the acidification of the tumor microenvironment. Human tumor cells often have increased V-type H(+)-ATPase expression and activity. PPI pretreatment inhibits these ATPases, sensitizing tumor cells to chemo drugs.13
Disrupting the pH gradient in tumors appears to prevent development of chemoresistance. PPIs are used to treat peptic disease because they inhibit acid secretion by targeting the gastric acid pump. But they also inhibit V-H(+)-ATPases. The classic PPIs are actually all weak bases that tend to accumulate in acidic spaces.14
In 2008, Morimura et al. reported that cancer cells are more sensitive to PPIs than normal cells and this sensitivity allows them to become a target of PPI therapy. Morimura, "… used cells of hepatoblastoma, the cancer type accounting for 80% of all childhood liver cancers, to investigate the effects of [PPIs]… as an inducer of cancer cell apoptosis and inhibitor of cancer cell reproduction." Treatment of hepatoblastoma cells with a PPI resulted in slower cell division and increased cancer cell apoptosis (suicide).15
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