Synergistic Interaction between the HDAC Inhibitor, MPT0E028, and Sorafenib in Liver Cancer Cells In Vitro and In Vivo

Abstract

Purpose To investigate the antitumor activities of a histone deacetylase (HDAC) inhibitor, MPT0E028, plus sorafenib in liver cancer cells in vitro and in vivo. Experimental Design Different liver cancer cell lines were exposed to sorafenib in the presence or absence of MPT0E028, and cell viability was determined by MTT assay. Effects of combined treatment on cell cycle and intracellular signaling pathways were assessed by flow cytometry and Western blot analysis. The Hep3B xenograft model was used to examine the antitumor activity in vivo. Results Our data indicate that sorafenib and MPT0E028 synergistically reduced cell viability in liver cancer cells, and also markedly induced apoptotic cell death in these cells, as evidenced by the cleavage of caspase-3, PARP, and DNA fragmentation. MPT0E028 altered the global modifications of histone and nonhistone proteins regardless of the presence of sorafenib. However, sorafenib blocked MPT0E028-induced Erk activation and its downstream signaling cascades, such as Stat3 phosphorylation (Ser727) and Mcl-1 upregulation. Ectopic expression of constitutively active Mek successively reversed the apoptosis triggered by the combined treatment. Pharmacologic inhibition of Mek by PD98059 potentiated MPT0E028-induced apoptosis, suggesting that the synergistic interaction between MPT0E028 and sorafenib occurs at least partly through inhibition of Erk signaling. The data demonstrated that transcriptional activation of fibroblast growth factor receptor 3 (FGFR3) contributes to MPT0E028-mediated Erk phosphorylation. Finally, MPT0E028 plus sorafenib significantly improved the tumor growth delay (TGD) in a Hep3B xenograft model. Conclusions These findings suggest that MPT0E028 in combination with sorafenib has significant anti-hepatocellular carcinoma activity in preclinical models, potentially suggesting a novel therapeutic strategy for patients with advanced hepatocellular carcinoma.

Novel oral histone deacetylase inhibitor, MPT0E028, displays potent growth-inhibitory activity against human B-cell lymphomain vitroandin vivo

“…Its antitumor activities include inducing apoptosis, HDAC activity inhibition, Akt pathway deactivation, and regulation of many genes in vitro ; and prolongation of survival rate and reduction of tumor volume in vivo . Our previous work [12-14] and current studies suggest that MPT0E028 has greater efficacy in vivo and in vitro compared to SAHA. In totality, our results provide compelling evidence that MPT0E028 can be an effective antitumor agent in the treatment of B-cell lymphoma.…”

“…Therefore, combinations with classical chemotherapeutic agents [43, 44] or new small molecule inhibitors [45] are being investigated. According to our previous study, MPT0E028 also showed synergism in combination with tyrosine kinase inhibitors, such as erlotinib and sorafenib, in non-small cell lung cancer (NSCLC) and liver cancer, respectively [13, 14]. Therefore, combination treatment with different therapeutic agents in solid tumors may broaden the potential usage of MPT0E028.…”

“…MPT0E028 (3-(1-Benzenesulfonyl-2,3-dihydro-1H-indol-5-yl)-N-hydroxy-acrylamide) is a novel HDAC inhibitor in vitro and in vivo with a potent and broad HDAC inhibitory effect in multiple human cancers, both alone and in combination with other treatments [12-14]. In this study, we show that MPT0E028 possesses a more potent inhibitory effect against HDACs and greater ability in targeting Akt compared with the HDAC inhibitor vorinostat (SAHA) in human B-cell lymphoma cells.…”

Synergistic activity of vorinostat combined with gefitinib but not with sorafenib in mutant KRAS human non-small cell lung cancers and hepatocarcinoma

“…Preclinical studies have demonstrated antiproliferative, antiangiogenic, and proapoptotic effects from combining HDAC inhibitors with sorafenib in epithelial tumor cells,19–21 including HCC cells 22. Several phase I studies investigated HDAC inhibitors in combination with sorafenib, and these studies either support future clinical development of an entinostat/sorafenib combination in patients with advanced solid tumors43 or show that the combined sorafenib and vorinostat treatment was not tolerated and had no confirmed response in patients with renal cell carcinoma and NSCLC 44.…”

“…However, the majority of HCC patients do not respond to sorafenib, and most, if not all, patients who initially respond to sorafenib develop tumor resistance after a few months of treatment 18. Preclinical studies have also shown that combining HDAC inhibitors with sorafenib can have antiproliferative, antiangiogenic, and proapoptotic effects on epithelial tumor cells including HCC cells 19–22…”