T090137 Inhibits Cisplatin-Induced Apoptosis in Ovarian Cancer Cells

• DOI: 10.1097/igc.0b013e318228f558
• Publication Date: 2011-10-04T22:02:38Z
• Authors: Daniel H. Miller; Andrew K. Fischer; Katrina F. Chu; Risa Burr; Sara Hillenmeyer; Laurent Brard; Alexander S. Brodsky
• Keywords: 0301 basic medicine; 0303 health sciences; 03 medical and health sciences; 3. Good health

Objective—To determine the function of T0901317 in combination treatment with cisplatin in ovarian cancer cells. Methods—We screened the effects of three nuclear hormone receptor ligands on cell viability in a panel of ovarian cancer cells lines. T0901317 regulation of apoptosis and cell cycle regulators was determined when applied as a single agent, or in combination with cisplatin. Results—Surprisingly, the LXR agonist T0901317 had no significant effects on a panel of seven ovarian cancer cell lines as a single agent. T0901317 does, however, significantly decrease cisplatin efficacy in at least three ovarian cancer cells lines. T0901317 reduces cisplatin induced apoptosis and reverses cisplatin induced expression of cell cycle regulators. T0901317 appears to work in an LXR, PXR, and FXR independent manner, as agonists of these nuclear hormone receptors did not show similar effects. Interestingly, in the A2780-cp drug resistant cell line, the effect of T0901317 is lost, suggesting that the pathways stimulated by T0901317 to reduce cisplatin efficacy could be inherently active features of the selected resistance. Conclusions—Together, these data suggest that T0901317 inhibits cisplatin in some ovarian cancer cells. These data provide an avenue to investigate when T0901317 may be acting to promote tumor survival and drug resistance through control of apoptosis, and when it may be acting as an anti-tumor agent, as has been previously reported.