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

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Author(s): Sarah Deleu | Joanna Fraczek | Aneta Lukaszuk | Tatyana Doktorova | Dirk Tourwé | Albert Geerts | Ben Van Camp | Tamara Vanhaecke | Vera Rogiers | Karin Vanderkerken

Journal: Journal of Cancer Molecules
ISSN 1816-0735

Volume: 4;
Issue: 4;
Start page: 117;
Date: 2008;
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Keywords: Trichostatin analogues | histone deacetylase | 5T33MM | Bax

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.
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