The Combination of Vemurafenib and Procaspase-3 Activation Is Synergistic in Mutant BRAF Melanomas.

ABSTRACT: The development of vemurafenib resistance limits the long-term efficacy of this drug for treatment of metastatic melanomas with the (V600E)BRAF mutation. Inhibition of downstream MAPK signaling with vemurafenib induces apoptotic cell death mediated by caspase-3, suggesting that addition of a procaspase-3 activator could enhance anticancer effects. Here, we show that the combination of PAC-1, a procaspase-activating compound, and vemurafenib is highly synergistic in enhancing caspase-3 activity and apoptotic cell death in melanoma cell lines harboring the (V600E)BRAF mutation. In vivo, the combination displays a favorable safety profile in mice and exerts significant antitumor effects. We further demonstrate that addition of PAC-1 to the clinically useful combination of vemurafenib and a ME

SUBMITTER: Peh J 

PROVIDER: S-EPMC4975653 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature