Reversing drug resistance in bcl-2-expressing tumor cells by depleting glutathione.

The immense research effort in cancer cell physiology has led to an appreciation of the molecular and biochemical pathways that regulate cellular responses to endogenous and exogenous insults. Similarly, in tumor cells, there are multiple overlapping pathways that, once activated, impart resistance to therapeutic intervention. The multi drug resistance pathway is one such pathway. In this review, we will present current ideas concerning a mechanism of tumor cell resistance that involves the inability to undergo apoptosis. The bcl-2 family of proteins are known to regulate apoptosis in response to a wide variety of toxic agents. Additionally, recent evidence points to bcl-2 involvement in the regulation of antioxidant pathways mediated by glutathione. This new information will be discussed in some detail and strategies for overcoming these resistance mechanisms that may have clinical utility will be presented.