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

ObjectivesTo evaluate the efficacy of combination of navitoclax, carboplatin and paclitaxel in ovarian cancer.Methods8 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.ResultsNavitoclax exhibited modest (IC50 = 3–8 μM) 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.ConclusionsNavitoclax improves the activity of combinations of carboplatin and paclitaxel in vitro. Our observations, taken with other published data, provide a rationale for clinical trials of navitoclax in ovarian cancer in combination with chemotherapy.

► Navitoclax combined with either carboplatin or paclitaxel inhibits cell growth more effectively than carboplatin and paclitaxel doublet combinations.
► In triplet combinations, navitoclax reduces the antagonism between carboplatin and paclitaxel.
► Navitoclax augments the activity of carboplatin and/or paclitaxel in Igrov-1 spheroids.