Repurposing Drugs for Cancer Treatment

Pharmaceutical manufacturers incur tremendous expense and deal with considerable risk when developing new drugs, especially drugs to be used in cancer. For this reason, many researchers are interested in looking at FDA-approved drugs that could potentially be repositioned for use in cancer treatment. This allows the drugs to enter clinical trials rapidly and lets researchers rely on previous pharmacokinetic, toxicological, and safety data.

The journal Cancer Chemotherapy and Pharmacology has published a review article that discusses repositioning of proton pump inhibitors (PPIs) in cancer treatment.

This topic is of interest to clinicians because PPIs have been around for decades, have favorable safety profiles, and are reasonably priced.

According to the authors, PPIs exert their anticancer effects in the tumor’s microenvironment. Tumor cells thrive on the chronic imbalance of cellular homeostasis and generally prefer an acidic extracellular environment that promotes tissue damage and activates destructive enzymes. This increases metastatic potential, and can also lead to multidrug resistance. Tumors actually select for cells that survive these extreme conditions, which in turn increases tumor aggression.

However, the intracellular tumor environment is not acidic. It’s alkaline. It stems from the tumor’s propensity to use more than normal amounts glucose, converting it to lactic acid and protons that accumulate in the cytoplasm.

The pH gradient between the extracellular and intracellular environments is regulated by ion/proton pump systems. For this reason, researchers suspect that PPIs may be able to reduce tumor activity.

V-ATPase is very important in tumor growth, and PPIs inhibit V-ATPase as they decrease the acidic environment by shutting down proton pumps.

The authors reviewed the evidence for PPI use in gastric, colorectal, esophageal, and pancreatic cancers. These are all cancers of the digestive system in which acidity plays a significant role. Additionally, the authors suggested that this new information may be important as we develop new treatments for breast cancer.

Areas where research is needed include PPIs’ molecular mechanisms that affect cancer, and how PPIs’ pro-drug transformation may affect or be affected by cancer treatment. In addition, it appears that PPI concentrations for anticancer purposes must be significantly higher than those used for gastrointestinal disease. The authors also noted concerns with the efficacy differences between PPIs in cancer and long-term safety.

References

Lu ZN, Tian B, Guo XL. Repositioning of proton pump inhibitors in cancer therapy. Cancer Chemother Pharmacol. 2017 Aug 31. doi: 10.1007/s00280-017-3426-2. [Epub ahead of print]