Shankar Eswar, Basu Chandreyi, Adkins Brett, Siede Wolfram, Basu Alakananda
Department of Molecular Biology and Immunology, University of North Texas, Health Science Center, Fort Worth, Texas, USA.
J Mol Signal. 2010 May 10;5:4. doi: 10.1186/1750-2187-5-4.
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.
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.
卵巢癌是妇科癌症中导致死亡的主要原因。顺铂是治疗卵巢癌最有效的抗癌药物之一。对顺铂产生耐药性限制了其治疗用途。包括顺铂在内的大多数抗癌药物被认为通过诱导细胞凋亡来杀死癌细胞，而凋亡信号传导缺陷可能导致耐药性。肿瘤抑制蛋白p53在DNA损伤诱导的细胞凋亡中起关键作用。在基于酵母的药物筛选过程中，发现NSC109268可增强细胞对顺铂的敏感性。本研究的目的是确定p53是否是NSC109268使顺铂增敏的原因。
NSC109268增强了表达野生型p53的卵巢癌2008细胞及其顺铂耐药对应细胞2008/C13细胞对顺铂的敏感性。与2008细胞相比，NSC109268对2008/C13细胞顺铂敏感性的增强作用更大。顺铂导致2008和2008/C13*细胞中p53浓度依赖性增加，并且p53的诱导与通过PARP裂解确定的顺铂诱导的细胞凋亡相关。单独的NSC109268对p53没有影响，但它增强了顺铂作用下的p53水平。然而，通过小干扰RNA敲低p53并没有减弱顺铂或NSC109268与顺铂联合作用诱导的细胞死亡。
这些结果表明，NSC109268增强卵巢癌2008细胞对顺铂的敏感性，且不依赖于p53。
