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

Authors

  • Yen-Shen Lu,

    1. Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy and Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210
    2. Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
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  • Yoko Kashida,

    1. Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy and Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210
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  • Samuel K. Kulp,

    1. Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy and Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210
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  • Yu-Chieh Wang,

    1. Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy and Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210
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  • Dasheng Wang,

    1. Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy and Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210
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  • Jui-Hsiang Hung,

    1. Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy and Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210
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  • Monica Tang,

    1. Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy and Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210
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  • Zhong-Zhe Lin,

    1. Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
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  • Te-Jung Chen,

    1. Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
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  • Ann-Lii Cheng,

    1. Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
    2. Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
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  • Ching-Shih Chen

    Corresponding author
    1. Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy and Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210
    • Division of Medicinal Chemistry, College of Pharmacy, L. M. Parks Hall, Ohio State University, 500 West 12th Avenue, Columbus, OH 43210
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    • fax: (614)688-8556


  • Potential conflict of interest: Nothing to report.

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 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 (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. (HEPATOLOGY 2007.)

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