The multiple mechanisms of multidrug resistance and cellular pH.

Abstract

Multidrug resistance (MDR) describes a variety of strategies that tumour cells develop to evade the cytotoxic effects of anti-cancer drugs. Tumour cells that have become MDR show decreased cellular sensitivity to the drug employed in chemotherapy as well as a broad spectrum of drugs without obvious common targets or structural homology. MDR is a major obstacle to the successful treatment of tumours. Our understanding of multidrug resistance is limited, in part, by our limited knowledge of what makes tumour cells more sensitive to chemotherapeutics. Drug resistance may subvert the same mechanisms that make tumour cells hypersensitive or use molecular modifications unrelated to the mechanisms that lead to hypersensitivity in tumour cells. Indeed, multidrug resistance is likely to be the consequence of a multitude of mechanisms. Some drug-resistant and drug-sensitive mammalian cell lines have shown aberrations in regulation of cellular pH. These changes can contribute to some of the physiological and cell biological changes that are observed both in drug-sensitive and MDR tumour cell lines. As such, at least in some tumour cell lines, the changes of pH contribute both to the physiology of transformation and the physiology of drug-resistance. The observation that these variations from normal pH are not universally observed in either tumour or MDR cells suggests that these mechanisms cannot be generalized to all transformed or MDR cells. It remains to be resolved to what extent these changes are a consequence of studying cell lines grown in vitro or if they reflect the in situ physiology of human tumours. There are no detectable changes in cytosolic or organellar pH in cells transfected with P-glycoprotein, a plasma membrane-based protein implicated in drug resistance. Thus, there are likely to be multiple mechanisms contributing to multiple drug-resistance.