OBJECTIVES: To evaluate the efficacy of combination of navitoclax, carboplatin and paclitaxel 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 (IC(50)=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. CONCLUSIONS: Navitoclax 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.
OBJECTIVES: To evaluate the efficacy of combination of navitoclax, carboplatin and paclitaxel 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 (IC(50)=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. CONCLUSIONS:Navitoclax 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.
Authors: Elizabeth H Stover; Maria B Baco; Ofir Cohen; Yvonne Y Li; Elizabeth L Christie; Mukta Bagul; Amy Goodale; Yenarae Lee; Sasha Pantel; Matthew G Rees; Guo Wei; Adam G Presser; Maya K Gelbard; Weiqun Zhang; Ioannis K Zervantonakis; Patrick D Bhola; Jeremy Ryan; Jennifer L Guerriero; Joan Montero; Felice J Liang; Andrew D Cherniack; Federica Piccioni; Ursula A Matulonis; David D L Bowtell; Kristopher A Sarosiek; Anthony Letai; Levi A Garraway; Cory M Johannessen; Matthew Meyerson Journal: Mol Cancer Res Date: 2019-08-28 Impact factor: 5.852
Authors: Vikram B Wali; Casey G Langdon; Matthew A Held; James T Platt; Gauri A Patwardhan; Anton Safonov; Bilge Aktas; Lajos Pusztai; David F Stern; Christos Hatzis Journal: Cancer Res Date: 2016-11-21 Impact factor: 12.701
Authors: Shuai Jiang; Amy W Pan; Tzu-yin Lin; Hongyong Zhang; Michael Malfatti; Kenneth Turteltaub; Paul T Henderson; Chong-xian Pan Journal: Chem Res Toxicol Date: 2015-11-11 Impact factor: 3.739