Carfilzomib Interacts Synergistically with Histone Deacetylase Inhibitors in Mantle Cell Lymphoma Cells In Vitro and In Vivo

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 vorinostat or SNDX-275 concentrations induced sharp increases in mitochondrial injury and apoptosis in multiple MCL cell lines and primary MCL cells. Enhanced lethalitly was associated with JNK1/2 activation, increased DNA damage (induction of λH2A.X), and ERK1/2 and AKT1/2 inactivation. Co-administration of carfilzomib and HDACIs induced a marked increase in ROS generation, and G2M arrest. Significantly, the free radical scavenger TBAP blocked carfilzomib/HDACI-mediated ROS generation, λH2A.X formation, JNK1/2 activation, and lethality. Genetic (shRNA) knock down of JNK1/2 significantly attenuated carfilzomib/HDACI-induced apoptosis, but did not prevent ROS generation or DNA damage. Carfilzomib/HDACI regimens were also active against bortezomib-resistant MCL cells. Finally, carfilzomib/vorinostat co-administrationo resulted in a pronounced reduction in tumor growth compared to single agent treatment in a MCL xenograft model associated with enhanced apoptosis, λH2A.X formation, and JNK activation. Collectively, these findings suggest that carfilzomib/HDACI regimens warrants attention in MCL.

Valproic acid, an anti-epileptic drug and a histone deacetylase inhibitor, in combination with proteasome inhibitors exerts antiproliferative, pro-apoptotic and chemosensitizing effects in human colorectal cancer cells: Underlying molecular mechanisms

“…In the present study, the co-administration of VPA with PI, MG132, PI-1 or PR-39 induced a marked increase in apoptosis in human colorectal cancer cells. Our results are consistent with those reported by other groups using several different cell systems and various combinations of HDACIs and PIs (1,15,22,35,39).…”

“…Co-administration of the antioxidant, L-NAC, (15 mM) substantially blocked the VPA/PI-mediated increase in ROS levels (data not shown). Our results are consistent with those of other studies using different combinations of HDACs and PIs in various cell systems (15,35). HDACIs have been shown to raise intracellular ROS levels (36), and our results indicated that the combination of VPA and PIs induced a greater increase in ROS levels than that observed with either agent alone.…”

“…Our results are in agreement with those reported in another study using the melanoma cell line, SK-Mel-37: the combination of VPA and hydroxyurea (HU) increased the number of cells in the S phase (38). The results from flow cytometry reported in that study are contradictory to those reported by other groups using several different cell systems and various combinations of HDACIs and PIs (35,39).…”

Histone deacetylase inhibitors in cancer therapy. A review

“…Proteasome inhibitor, marizomib in combination with vorinostat or entinostat increased apoptosis in several leukemia cells, caspase 8 activation and oxidative stress contributed to the synergistic effects 45 . In vitro and in vivo studies with diffuse large B cell lymphoma and mantle cell lymphoma cells including bortezomib resistant ones showed that another proteasome inhibitor, carfilzomib, increased the effects of vorinostat 76,77 . 5) Numerous studies show synergisms or additive effects combining the HDAC inhibitors and DNAdamaging agents such as topoisomerase inhibitors, DNAintercalators, inhibitors of DNA synthesis and agents covalently modifying DNA (i.e.…”

New Therapies in T-cell Lymphoma

“…29 This can be abrogated by HDAC6 mediated targeting of these proteins to aggresomes with resulting degradation through activation of autophagy. There is therefore a considerable rationale in combining an HDAC inhibitor with a proteasome inhibitor 30,31 and trials in PTCL are ongoing.…”