Abstract B67: Thapsigargin sensitizes multidrug‐resistant human ovarian carcinoma cells to doxorubicin

Chemoresistance to anticancer drugs is a common and troublesome occurrence in ovarian cancer patients. Despite advances in surgical and chemotherapeutic modalities, survival rates remain alarmingly low. Hence, it has been suggested that strategies for reversing multidrug resistance (MDR) are top priorities for reducing cancer mortality. Thapsigargin (TG), a sesquiterpene lactone isolated from the roots of Thapsia garganica , has been demonstrated to possess anticancer properties. The impact of TG, however, on chemoresistance has not been fully elucidated. Here, we report the effects of combining TG with doxorubicin (DOX), since DOX forms part of the standard treatment for women with advanced ovarian cancer. Multidrug‐resistant A2780/MDR human ovarian carcinoma cells were treated with TG in combination with a clinically relevant concentration of DOX (10 µM) and assessed for cell proliferation using the MTT assay. A2780/MDR cells were 100‐fold more resistant to DOX than parental A2780 cells on the basis of MTT assay. The IC50 of DOX decreased from 8.02 µM to 0.07 µM, in the presence of 1 µMTG, after 24 h of continuous drug combination exposure, producing a 115‐fold reversal of MDR. Flow cytometric analysis of cells treated for 24 h with 10 µM DOX with and without 5 µMTG demonstrated significantly increased apoptosis in the presence of TG. TG by itself had little effect on the viability of A2780/MDR cells, as evident by less than 5% cell death after 24‐h TG treatment. The activation of caspases‐3 and ‐9 and PARP cleavage were enhanced in combination therapy relative to single agent treatments. Combined treatment with TG and DOX also increased JNK phosphorylation in A2780/MDR cells and pretreatment with JNK inhibitor SP600125 partially rescued apoptosis. Our data demonstrated that addition of TG at subtoxic concentration restored the sensitivity to DOX‐induced apoptosis in A2780/MDR cells via JNK pathway. Taken together, these data support the concurrent use of DOX and TG in ovarian cancer therapeutics. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B67.