Navitoclax augments the activity of carboplatin and paclitaxel combinations in ovarian cancer cells

Objectives. To evaluate the efficacy of combination of navitoclax, carboplatin and paditaxel in ovarian cancer. Methods. 8 ovarian cancer cell lines were treated with either doublet or triplet combinations of navitoclax, carboplatin and paclitaxel. Interactions were assessed by determining a combination index or measuring caspase activity. The effect of the combinations was also evaluated by measuring the inhibition of cells grown as spheroids. Results. Navitoclax exhibited modest (IC50 = 3-8 mu M) single agent potency. Antagonism between carboplatin and paclitaxel was evident in Ovcar-4, Ovcar-8 and Skov-3 cells. Drug combinations including navitoclax with carboplatin and/or paclitaxel showed significantly less antagonism, or even synergy, in several cell lines than carboplatin/paclitaxel alone. Navitoclax enhanced the activation of caspase 3/7 induced by carboplatin and/or paclitaxel in Igrov-1 cells. Combinations of navitoclax, carboplatin and paclitaxel showed more than additive activity against Igrov-1 spheroids. Conclusions. Navitoclax improves the activity of combinations of carboplatin and paditaxel in vitro. Our observations, taken with other published data, provide a rationale for clinical trials of navitoclax in ovarian cancer in combination with chemotherapy. (C) 2012 Elsevier Inc. All rights reserved.