Synergistic interaction between the HDAC inhibitor, MPT0E028, and sorafenib in liver cancer cells in vitro and in vivo

Chun Han Chen, Mei Chuan Chen, Jing Chi Wang, An Chi Tsai, Ching Shih Chen, Jing Ping Liou, Shiow Lin Pan, Che Ming Teng

Research output: Contribution to journalArticle

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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 byMTTassay. 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 antihepatocellular carcinoma activity in preclinical models, potentially suggesting a novel therapeutic strategy for patients with advanced hepatocellular carcinoma.

Original languageEnglish
Pages (from-to)1274-1287
Number of pages14
JournalClinical Cancer Research
Volume20
Issue number5
DOIs
Publication statusPublished - 2014

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Histone Deacetylase Inhibitors
Liver Neoplasms
Heterografts
Cell Survival
Histone Code
Receptor, Fibroblast Growth Factor, Type 3
Phosphorylation
sorafenib
3-(1-benzenesulfonyl-2,3-dihydro-1H-indol-5-yl)-N-hydroxyacrylamide
In Vitro Techniques
Apoptosis
DNA Fragmentation
Caspase 3
Transcriptional Activation
Hepatocellular Carcinoma
Cell Cycle
Flow Cytometry
Cell Death
Research Design
Up-Regulation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Synergistic interaction between the HDAC inhibitor, MPT0E028, and sorafenib in liver cancer cells in vitro and in vivo. / Chen, Chun Han; Chen, Mei Chuan; Wang, Jing Chi; Tsai, An Chi; Chen, Ching Shih; Liou, Jing Ping; Pan, Shiow Lin; Teng, Che Ming.

In: Clinical Cancer Research, Vol. 20, No. 5, 2014, p. 1274-1287.

Research output: Contribution to journalArticle

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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 byMTTassay. 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 antihepatocellular carcinoma activity in preclinical models, potentially suggesting a novel therapeutic strategy for patients with advanced hepatocellular carcinoma.",
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T1 - Synergistic interaction between the HDAC inhibitor, MPT0E028, and sorafenib in liver cancer cells in vitro and in vivo

AU - Chen, Chun Han

AU - Chen, Mei Chuan

AU - Wang, Jing Chi

AU - Tsai, An Chi

AU - Chen, Ching Shih

AU - Liou, Jing Ping

AU - Pan, Shiow Lin

AU - Teng, Che Ming

PY - 2014

Y1 - 2014

N2 - 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 byMTTassay. 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 antihepatocellular carcinoma activity in preclinical models, potentially suggesting a novel therapeutic strategy for patients with advanced hepatocellular carcinoma.

AB - 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 byMTTassay. 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 antihepatocellular carcinoma activity in preclinical models, potentially suggesting a novel therapeutic strategy for patients with advanced hepatocellular carcinoma.

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