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

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

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Abstract

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 anti-tumor 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 (IC50) 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 mm3) 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.

Original languageEnglish
Pages (from-to)1119-1130
Number of pages12
JournalHepatology
Volume46
Issue number4
DOIs
StatePublished - Oct 2007

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    Lu, Y. S., Kashida, Y., Kulp, S. K., Wang, Y. C., Wang, D., Hung, J. H., Tang, M., Lin, Z. Z., Chen, T. J., Cheng, A. L., & Chen, C. S. (2007). Efficacy of a novel histone deacetylase inhibitor in murine models of hepatocellular carcinoma. Hepatology, 46(4), 1119-1130. https://doi.org/10.1002/hep.21804