The pH gradient reversal found in the microenvironment of cancers is often responsible for decreased efficacy of a wide variety of cancer drugs, leading to drug resistance for many chemotherapies and radiotherapies41. Many cancer drugs are weak bases, and must pass through the cell membrane to reach their intracellular target protein. As the pHe around cancer cells is very acidic, the ratio of positively charged drug/neutral drug increases, decreasing the drugs ability to enter the cancer cell and reach its therapeutic target (figure 2). Even if the drug passes through the cell membrane, it is then most likely to be sequestered and trapped in a more acidic organelle of the cell, such as the lysosome, where it will be degraded42,43. This relationship between the acidity or basicity of a drug and the pH microenvironment of the cancer cell implies that weakly acidic drugs would be ionized to a smaller degree and be able to pass through the cell membrane more easily. This has been shown to be the case for chlorambucil, which exhibits increased cytotoxicity when the pHe is more acidic44.

            While designing cancer drugs as weak acids instead of weak bases may increase their efficacy in the altered pH microenvironment of the cancer cell, drug resistance is still certainly possible due to the presence of drug efflux pumps. The efflux pump Breast Cancer Resistance Protein (ABCG2) has been shown to more efficiently pump cancer drugs out of the cell at a lower pHe45. Additionally, the efflux pump P-glycoprotein exhibits pH-dependent activity45, although the precise effects of its activity on the neutral and charged forms of weakly acidic and basic drugs is still unclear. A potential strategy to circumvent this is the co-treatment of cancer drugs with an efflux pump inhibitor.

            Instead of designing cancer drugs that are more active in the pH-dysregulated environment of cancer, another increasingly popular strategy is to design drugs that actively try to restore the regular pH properties of cells. Knockout, knockdown and/or inhibition studies have been performed on a variety of the pH regulating proteins discussed above, including Na+/H+ exchangers (NHE1)46, monocarboxylate transporters (MCT1/2)47, and carbonic anhydrases (CAIX)48, many of which hold promising therapeutic potential. As discussed, CAIX and MCT1 cooperate to increase proton and lactate flux49, illustrating the importance of understanding not only structural data of drug targets, but their mechanistic modes of action as well.

A more non-targeted approach toward restoring normal pH levels has also been considered. This approach is known as buffer therapy, and involves ingestion of bicarbonate or similar buffers, which helps increase pHe by sequestering protons50. This approach has been shown to effectively increase pHe and prevent metastases51, and is particularly promising considering that redundancy of pH regulatory proteins may decrease the effectiveness of more targeted approaches.

No two cancers are completely identical, highlighting the importance of different therapeutic strategies. While problems in the above therapeutic strategies still exist, recent advancements indicate that they hold great potential for restoring normal pH levels in cancers. A combination of the above approaches, in tandem with current anticancer drugs, may prove to be very effective in fighting cancers.

 

            pH is critical for cellular processes, as every enzyme’s activity is a function of pH. As such, the dysregulation of pH is expected to lead to suboptimal cellular behavior, as described above in cancer. In recent years, the field of pH dysregulation in cancer has greatly improved our understanding of this critical hallmark of cancer, particularly with the characterization of pH sensors, yet there remains a lot to be discovered. Moving forward, it will be important to consider how redox state is altered in the cancer environment in addition to pH, as it is known that redox potential and pH are closely intertwined52,53. To date, their combined, and possibly synergistic, effect in cancer has been largely ignored. Additionally, the field would benefit greatly from the generation of improved tools to detect pH changes over short and long spatial and temporal scales. The prospect of saving lives and halting disease in its tracks will continue to fuel the field of pH regulation in cancer as we work to broaden our understanding from fundamentals to clinical trials.