BACKGROUND Ovarian cancer is the leading cause of death among gynecological cancers. Cisplatin is one of the most effective anticancer drugs used in the treatment of ovarian cancer. Development of resistance to cisplatin limits its therapeutic use. Most of the anticancer drugs, including cisplatin, are believed to kill cancer cells by inducing apoptosis and a defect in apoptotic signaling can contribute to drug resistance. The tumor suppressor protein p53 plays a critical role in DNA damage-induced apoptosis. During a yeast-based drug screening, NSC109268 was identified to enhance cellular sensitivity to cisplatin. The objective of the present study is to determine if p53 is responsible for cisplatin sensitization by NSC109268. RESULTS 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. CONCLUSIONS These results demonstrate that NSC109268 enhances sensitivity of ovarian cancer 2008 cells to cisplatin independent of p53.