Abstract 1713: Mechanisms of resistance to platinum based drugs uncovered by protection caused by substituted coumarins

Abstract Disruption of p53 can have a profound effect on cellular sensitivity to Platinum-based drugs. Inhibition of NQO1 by dicoumarol and other substituted coumarins can target p53 for degradation. Thus, we tested the ability of NQO1 inhibitors to protect HCT116 cells (containing wild type p53) against the cytotoxic effects of cisplatin. All the NQO1 inhibitors protect cells against the damaging effects of cisplatin (see the table for representative data for one of the inhibitors, AS3). Protection was also seen in a second cell line with wild type p53 (RT112 bladder carcinoma cells). To confirm p53 dependence, experiments were carried out using cells with mutant (MDA231) or null (HCT116 -/-) p53. Surprisingly, the coumarin-based agents also protected these cells against cisplatin-induced damage. In addition, these observations were not dependent on NQO1, since MDA231 cells, with negligible NQO1, and cells overexpressing NQO1 (MDA321-DTD) were similarly protected. Protection is also observed for oxaliplatin but, interestingly, there is no protection against etoposide toxicity. Cell cycle analysis of HCT116 cells treated with cisplatin show that, 24 hours after treatment, cells are blocked in G2. When cells are given the dicoumarol analogues at the same time as the cisplatin, no cell cycle delay is observed. Further, analysis of apoptosis mediators shows that treatment with AS3 inhibits oxaliplatin induction of Bak and reduces caspase-3 activity. Understanding the mechanism by which treatment with the dicoumarol analogues can cause resistance to cisplatin could reveal new methods for potentially overcoming resistance to platinum-based drugs in the clinic. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1713. doi:10.1158/1538-7445.AM2011-1713