Abstract
Multidrug resistance (MDR) mediated by the ATP‐dependent efflux protein P‐glycoprotein (P‐gp) is a major obstacle to the successful treatment of many cancers. In addition to effluxing toxins, P‐gp has been shown to protect tumor cells against caspase‐dependent apoptosis mediated by Fas and tumor necrosis factor receptor (TNFR) ligation, serum starvation and ultraviolet (UV) irradiation. However, P‐gp does not protect against caspase‐independent cell death mediated by granzyme B or pore‐forming proteins (perforin, pneumolysin and activated complement). We examined the effects of the chemotherapeutic hybrid polar compound suberoylanilide hydroxamic acid (SAHA) on P‐gp‐expressing MDR human tumor cell lines. In the CEM T‐cell line, SAHA, a histone deacetylase inhibitor, induced equivalent death in P‐gp‐positive cells compared with P‐gp‐negative cells. Cell death was marked by the caspase‐independent release of cytochrome c, reactive oxygen species (ROS) production and Bid cleavage that was not affected by P‐gp expression. However, consistent with our previous findings, SAHA‐induced caspase activation was inhibited in P‐gp‐expressing cells. These data provide evidence that P‐gp inhibits caspase activation after chemotherapeutic drug treatment and demonstrates that SAHA may be of value for the treatment of P‐gp‐expressing MDR cancers. © 2002 Wiley‐Liss, Inc.