Efficacy of a novel histone deacetylase inhibitor in murine models of hepatocellular carcinoma.

Abstract

UNLABELLED:

Hepatocellular carcinoma (HCC) is a leading cause of cancer death worldwide, yet effective therapeutic options for advanced HCC are limited. This study was aimed at assessing the antitumor effect of a novel phenylbutyrate-derived histone deacetylase (HDAC) inhibitor, OSU-HDAC42, vis-à-vis suberoylanilide hydroxamic acid (SAHA), in in vitro and in vivo models of human HCC. OSU-HDAC42 was several times more potent than SAHA in suppressing the viability of PLC5, Huh7, and Hep3B cells with submicromolar median inhibitory concentration (IC(50)) values. With respect to SAHA, OSU-HDAC42 exhibited greater apoptogenic potency, which was associated with reduced levels of the apoptotic regulators phosphorylated Akt B-cell lymphoma-xL, survivin, cellular inhibitor of apoptosis protein 1, and cellular inhibitor of apoptosis protein 2. The in vivo efficacy of OSU-HDAC42 versus SAHA was assessed in orthotopic and subcutaneous xenograft tumor models in athymic nude mice. Daily oral treatments with OSU-HDAC42 and SAHA, both at 25 mg/kg, suppressed the growth of orthotopic PLC5 tumor xenografts by 91% and 66%, respectively, and of established subcutaneous PLC5 tumor xenografts by 85% and 56%, respectively. This differential tumor suppression correlated with the modulation of intratumoral biomarkers associated with HDAC inhibition and apoptosis regulation. Moreover, the oral administration of OSU-HDAC42 at 50 mg/kg every other day markedly suppressed ectopic tumor growth in mice bearing large tumor burdens (500 mm(3)) at the start of treatment.

CONCLUSION:

OSU-HDAC42 is a potent, orally bioavailable inhibitor of HDAC with a broad spectrum of antitumor activity that includes targets regulating multiple aspects of cancer cell survival. These results suggest that OSU-HDAC42 has clinical value in therapeutic strategies for HCC.

• Authors: Yen-Shen Lu, Yoko Kashida, Samuel K Kulp, Yu-Chieh Wang, Dasheng Wang, Jui-Hsiang Hung, Monica Tang, Zhong-Zhe Lin, Te-Jung Chen, Ann-Lii Cheng, Ching-Shih Chen
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 46 Issue 4 Pg. 1119-30 (Oct 2007) ISSN: 0270-9139 [Print] United States
• PMID: 17654699 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• Inhibitor of Apoptosis Proteins
• Isoenzymes
• bcl-X Protein
• Vorinostat
• Proto-Oncogene Proteins c-akt
• Histone Deacetylases

Topics

• Animals
• Apoptosis (drug effects)
• Carcinoma, Hepatocellular (drug therapy, pathology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Disease Models, Animal
• Female
• Histone Deacetylase Inhibitors
• Histone Deacetylases (metabolism)
• Humans
• Hydroxamic Acids (pharmacology)
• Inhibitor of Apoptosis Proteins (metabolism)
• Isoenzymes (metabolism)
• Liver Neoplasms (drug therapy, pathology)
• Mice
• Mice, Nude
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction
• Transplantation, Heterologous
• Vorinostat
• bcl-X Protein (metabolism)