Preclinical screening of histone deacetylase inhibitors combined with ABT-737, rhTRAIL/MD5-1 or 5-azacytidine using syngeneic Vk*MYC multiple myeloma

G. M. Matthews, M. Lefebure, M. A. Doyle, J. Shortt, J. Ellul, M. Chesi, K. M. Banks, E. Vidacs, D. Faulkner, P. Atadja, P. L. Bergsagel, R. W. Johnstone

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

Multiple myeloma (MM) is an incurable malignancy with an unmet need for innovative treatment options. Histone deacetylase inhibitors (HDACi) are a new class of anticancer agent that have demonstrated activity in hematological malignancies. Here, we investigated the efficacy and safety of HDACi (vorinostat, panobinostat, romidepsin) and novel combination therapies using in vitro human MM cell lines and in vivo preclinical screening utilizing syngeneic transplanted Vk*MYC MM. HDACi were combined with ABT-737, which targets the intrinsic apoptosis pathway, recombinant human tumour necrosis factor-related apoptosis-inducing ligand (rhTRAIL/MD5-1), that activates the extrinsic apoptosis pathway or the DNA methyl transferase inhibitor 5-azacytidine. We demonstrate that in vitro cell line-based studies provide some insight into drug activity and combination therapies that synergistically kill MM cells; however, they do not always predict in vivo preclinical efficacy or toxicity. Importantly, utilizing transplanted Vk*MYC MM, we report that panobinostat and 5-azacytidine synergize to prolong the survival of tumor-bearing mice. In contrast, combined HDACi/rhTRAIL-based strategies, while efficacious, demonstrated on-target dose-limiting toxicities that precluded prolonged treatment. Taken together, our studies provide evidence that the transplanted Vk*MYC model of MM is a useful screening tool for anti-MM drugs and should aid in the prioritization of novel drug testing in the clinic.

Original languageEnglish (US)
Article numbere798
JournalCell Death and Disease
Volume4
Issue number9
DOIs
StatePublished - Sep 1 2013

Keywords

  • DNA methylation
  • Extrinsic apoptosis
  • Histone deacetylase inhibitors
  • Intrinsic apoptosis
  • Multiple myeloma

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

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    Matthews, G. M., Lefebure, M., Doyle, M. A., Shortt, J., Ellul, J., Chesi, M., Banks, K. M., Vidacs, E., Faulkner, D., Atadja, P., Bergsagel, P. L., & Johnstone, R. W. (2013). Preclinical screening of histone deacetylase inhibitors combined with ABT-737, rhTRAIL/MD5-1 or 5-azacytidine using syngeneic Vk*MYC multiple myeloma. Cell Death and Disease, 4(9), [e798]. https://doi.org/10.1038/cddis.2013.306