J. Cancer Mol. 4: 117-121, 2008

[Research Paper]

Screening of Trichostatin Analogues Based on Cellular Potency in the Murine Multiple Myeloma 5T33MM Model

Sarah Deleu¹, Joanna Fraczek¹, Aneta Lukaszuk, Tatyana Doktorova, Dirk Tourwé, Albert Geerts, Ben Van Camp, Tamara Vanhaecke, Vera Rogiers, and Karin Vanderkerken²

Departments of Hematology and Immunology [S. Deleu, B. Van Camp, K. Vanderkerken], Toxicology [J. Fraczek, T. Doktorova, T. Vanhaecke, V. Rogiers], Organic Chemistry [A. Lukaszuk, D. Tourwé], and Cell Biology [A. Geerts], Vrije University Brussel (VUB), Brussels, Belgium

Abstract:

AIM: To evaluate the screening of histone deacetylase inhibitors (HDACi) based on cellular potency using the murine multiple myeloma 5T33MM model.

METHODS: The cellular potencies of 10 structurally related compounds of the natural HDACi Trichostatin (TSA) were screened by measuring the DNA synthesis in primary murine 5T33MMvv cells.  The anti-tumor activity of the three most potent analogues was further confirmed in the 5T33MMvt cell line using proliferation, viability and active caspase-3 assays.  The data of this 5T33MM model were compared with the HDAC IC₅₀ of these compounds which were preliminarily determined in normal hepatocyte extract.

   RESULTS: The TSA analogues with a tetranoic spacer (compounds 7-10) had no significant effect on the DNA synthesis of 5T33MM cells, whereas the three most potent analogues (compounds 1, 3 and 4), having a pentanoic spacer, significantly reduced the DNA synthesis and the viability.  We further observed a significant increase of active caspase-3 in the 5T33MM cells when treated with compound 3 or 4, reflecting their apoptosis-inducing capability.  When comparing with the HDAC-inhibitory activities of these compounds in normal hepatocyte extract, a similar result was obtained to suggest that compound 4 had the most potent anti-cancer activity.

CONCLUSION: Screening the cellular potency of TSA analogues using the 5T33MM model is a reliable and efficient system to select the most potent analogue early in the development of HDACi and proves the value of this model for evaluation of HDACi.

Received 7/4/08; Revised 10/15/08; Accepted 10/17/08. 

¹These authors equally contributed to this study.

²Correspondence: Prof. Karin Vanderkerken, Department of Hematology and Immunology, Vrije Universiteit Brussel (VUB), Laarbeeklaan103, B-1090 Brussels, Belgium. Phone: 32-2-4774418. Fax: 32-2-4774405. E-mail: Karin.Vanderkerken@vub.ac.be

³Abbreviations: MM, multiple myeloma; BM, bone marrow; HDACi, histone deacetylase inhibitor(s); TSA, Trichostatin.

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