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      1. Author :
        Dasmahapatra, G.; Lembersky, D.; Son, M. P.; Attkisson, E.; Dent, P.; Fisher, R. I.; Friedberg, J. W.; Grant, S.
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        Journal Article
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      5. Publication :
        Molecular cancer therapeutics
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      12. Abstract :
        Interactions between the proteasome inhibitor carfilzomib and the HDAC inhibitors vorinostat and SNDX-275 were examined in mantle cell lymphoma (MCL) cells in vitro and in vivo. Co-administration of very low, marginally toxic carfilzomib concentrations (e.g., 3-4 nM) with minimally lethal concentrations of vorinostat or SNDX-275 resulted in sharp increases in mitochondrial injury and apoptosis in multiple MCL cell lines and primary MCL cells. Potentiation of cell death was associated with activation of JNK1/2, increased DNA damage, reflected by induction of lambdaH2A.X, and inactivation of ERK1/2 and AKT1/2. Co-administration of carfilzomib and HDACIs resulted in a marked increase in ROS generation, and arrest of cells in G2M. Significantly, the free radical scavenger TBAP blocked carfilzomib/HDACI-mediated ROS generation, lambdaH2A.X formation, JNK1/2 activation, and lethality. Genetic (shRNA) knock down of JNK1/2 significantly attenuated carfilzomib/HDACI-induced apoptosis in MCL cells, but did not prevent ROS generation or DNA damage. Carfilzomib/HDACI regimens were also active against bortezomib-resistant MCL cells. Finally, co-administration of carfilzomib and vorinostat resulted in a pronounced reduction in tumor growth compared to single agent treatment in a MCL xenograft model associated with enhanced apoptosis, lambdaH2A.X formation, and JNK activation. Collectively, these findings suggest that carfilzomib/HDACI regimens warrant attention in MCL.
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