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Sustained inhibition of deacetylases is required for the antitumor activity of the histone deactylase inhibitors panobinostat and vorinostat in models of colorectal cancer

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Summary

Despite compelling preclinical data in colorectal cancer (CRC), the efficacy of HDACIs has been disappointing in the clinic. The goal of this study was to evaluate the effectiveness of vorinostat and panobinostat in a dose- and exposure-dependent manner in order to better understand the dynamics of drug action and antitumor efficacy. In a standard 72 h drug exposure MTS assay, notable concentration-dependent antiproliferative effects were observed in the IC50 range of 1.2–2.8 μmol/L for vorinostat and 5.1–17.5 nmol/L for panobinostat. However, shorter clinically relevant exposures of 3 or 6 h failed to elicit any significant growth inhibition and in most cases a >24 h exposure to vorinostat or panobinostat was required to induce a sigmoidal dose–response. Similar results were observed in colony formation assays where ≥24 h of exposure was required to effectively reduce colony formation. Induction of acetyl-H3, acetyl-H4 and p21 by vorinostat were transient and rapidly reversed within 12 h of drug removal. In contrast, panobinostat-induced acetyl-H3, acetyl-H4, and p21 persisted for 48 h after an initial 3 h exposure. Treatment of HCT116 xenografts with panobinostat induced significant increases in acetyl-H3 and downregulation of thymidylate synthase after treatment. Although HDACIs exert both potent growth inhibition and cytotoxic effects when CRC cells were exposed to drug for ≥24 h, these cells demonstrate an inherent ability to survive HDACI concentrations and exposure times that exceed those clinically achievable. Continued efforts to develop novel HDACIs with improved pharmacokinetics/phamacodynamics, enhanced intratumoral delivery and class/isoform-specificity are needed to improve the therapeutic potential of HDACIs and HDACI-based combination regimens in solid tumors.

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Abbreviations

CRC:

Colorectal cancer

CTCL:

Cutaneous T-cell lymphoma

HDAC:

Histone deacetylase

HDACI:

Histone deacetylase inhibitor

HAT:

Histone acetyl transferase

IC:

Inhibitory concentration

PK:

Pharmacokinetic

PD:

Pharmacodynamic

TS:

Thymidylate synthase (protein)

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Acknowledgments

This research was funded by NCI CCSG (grant number 5 P30 CA014089) and the Robert E. Burns Memorial Foundation. The authors are grateful to Kathleen N. Beasley for her critical review of this manuscript.

Conflict of interest

All authors declare that they have no relevant conflict of interest.

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Authors and Affiliations

  1. Department of Pathology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA

    Peter M. Wilson & Robert D. Ladner

  2. Azusa Pacific University School of Biology and Chemistry, Azusa, CA, USA

    Melissa J. LaBonte, Shelby C. Martin & Stephanie T. Kuwahara

  3. Norris Comprehensive Cancer Center Division of Medical Oncology, University of Southern California, Los Angeles, CA, USA

    Anthony El-Khoueiry & Heinz-Josef Lenz

  4. Department of Pathology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Room 5322, Los Angeles, CA, 90089, USA

    Robert D. Ladner

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  1. Peter M. Wilson
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Correspondence to Robert D. Ladner.

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Wilson, P.M., LaBonte, M.J., Martin, S.C. et al. Sustained inhibition of deacetylases is required for the antitumor activity of the histone deactylase inhibitors panobinostat and vorinostat in models of colorectal cancer. Invest New Drugs 31, 845–857 (2013). https://doi.org/10.1007/s10637-012-9914-7

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  • DOI: https://doi.org/10.1007/s10637-012-9914-7

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