Therapeutic implications of tumor interstitial acidification

Interstitial acidification is a hallmark of solid tumor tissues resulting from the combination of different factors, including cellular buffering systems, defective tissue perfusion and high rates of cellular metabolism. Besides contributing to tumor pathogenesis and promoting tumor progression, tumor acidosis constitutes an important intrinsic and extrinsic mechanism modulating therapy sensitivity and drug resistance. In fact, pharmacological properties of anticancer drugs can be affected not only by tissue structure and organization but also by the distribution of the interstitial tumor pH. The acidic tumor environment is believed to create a chemical barrier that limits the effects and activity of many anticancer drugs. In this review article we will discuss the general protumorigenic effects of acidosis, the role of tumor acidosis in the modulation of therapeutic efficacy and potential strategies to overcome pH-dependent therapy-resistance.