Abstract B39: Multidrug resistant ovarian cancer cells are less susceptible to orlistat-induced cell death

In the United States, there will be over 21,000 new cases and more than 15,000 deaths from ovarian cancer in 2008. With a 70% death rate within one year of diagnosis, ovarian cancer is righteously coined the ‘silent killer.’ Multidrug resistance (MDR) and the lack of effective alternate drug treatments pose further serious dilemmas to ovarian cancer patients. Orlistat, an anti-obesity drug, functions by inhibiting fatty acid synthase (FASN), an enzyme up-regulated in approximately 50% of cancers. Current research indicates that orlistat preferentially destroys cancer cells via an apoptotic mechanism; however, the exact pathway of orlistat-induced tumor cell death is unclear. Our objective is to elucidate the basic mechanism of orlistatinduced cell death so that an emerging class of new drugs (FASN inhibitors) can be better tailored to treat ovarian cancer patients. The ovarian cancer lines OVCAR-8 and NCI/ADR (OVCAR-8 drug-resistant) were treated with increasing concentrations of orlistat over a period of 96 hrs. We hypothesized that the MDR cells will undergo less cell death compared to the sensitive ovarian cancer cells with orlistat. Using a combination of three different cell proliferation/death assays, it was determined that MDR cells are more robust and have increased proliferative capacity compared to the OVCAR-8 cells under equivalent conditions of orlistat treatment. In contrast, additional results by immunoblotting show that orlistat can more effectively reduce FASN protein expression over time. Furthermore, orlistat can induce an endoplasmic reticulum stress-response by up-regulating GRP78/BiP. Taken together, our data demonstrates that MDR ovarian cancer cells are not as susceptible to orlistat-induced cell death despite increased FASN reduction and this suggests that alternative stress-response or survival pathways may be active.