%0 Journal Article
%T Screening of Trichostatin Analogues Based on Cellular Potency in the Murine Multiple Myeloma 5T33MM Model
%A Sarah Deleu
%A Joanna Fraczek
%A Aneta Lukaszuk
%A Tatyana Doktorova
%J Journal of Cancer Molecules
%D 2008
%I 
%X 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.
%K Trichostatin analogues
%K histone deacetylase
%K 5T33MM
%K Bax
%U http://www.mupnet.com/JOCM%204(4)%20117-121.pdf