NSC109268 potentiates cisplatin-induced cell death in a p53-independent manner

NSC109268 enhanced sensitivity of ovarian cancer 2008 cells and its cisplatin resistant counterpart 2008/C13* cells which express wild-type p53. The potentiation of cisplatin sensitivity by NSC109268 was greater in 2008/C13* cells compared to 2008 cells. Cisplatin caused a concentration-dependent increase in p53 in 2008 and 2008/C13* cells, and the induction of p53 correlated with cisplatin-induced apoptosis as determined by the cleavage of PARP. NSC109268 alone had no effect on p53 but it enhanced p53 level in response to cisplatin. Knockdown of p53 by siRNA, however, did not attenuate cell death in response to cisplatin or combination of NSC109268 and cisplatin.These results demonstrate that NSC109268 enhances sensitivity of ovarian cancer 2008 cells to cisplatin independent of p53.cis-Diamminedichloroplatinum(II) or cisplatin is one of the most important anticancer drugs used in the treatment of solid tumors, especially ovarian, testicular, cervical and small cell lung carcinomas. Dose-limiting toxicity to normal tissues and acquisition of resistance by tumor tissues to cisplatin, however, poses a significant problem in cisplatin therapy. Identification of agents that can sensitize tumor cells to cisplatin, and circumvent or prevent cisplatin resistance should have significant impact in cisplatin-based therapy.The anticancer activity of cisplatin is believed to be due to its interaction with chromosomal DNA [1]. However, only a small fraction of cisplatin actually interacts with DNA, and inhibition of DNA replication cannot solely account for its biological activity [2]. The effectiveness of anticancer agents depends not only on their ability to induce DNA damage but also on the cell's ability to detect and respond to DNA damage [3,4]. The tumor suppressor protein p53 plays a critical role in DNA damage signaling [5]. It is activated in response to DNA damage and triggers transcription of genes involved in cell cycle, apoptosis, senescence and DNA repair [6,7]. T