INTRODUCTION: The subsequent administration of DNA methyltransferase (DNMT) inhibitors and Histone deacetylase HDAC inhibitors has significant effectiveness against blood cancers. Nevertheless the mechanisms behind these actions are still a controversial issue. ENTINOSTAT †A POWERFUL HDAC INHIBITOR: Entinostat (MS-275) is a powerful HDAC inhibitor, which is used orally. This molecule has longer half-life and it has proven anticancer activity that has been tested in different preclinical trials. The usage of Entinostat has shown increased acetylation of H4 [18]. Nevertheless, this molecule has demonstrated very limited activity against advanced leukemic cancers when used alone and without any combination [1]. ENTINOSTAT †WHAT IT DOES? Although Entinostat develops an overall decline in methylation, it does not produce the significant shift of expressions of genes even after couple of weeks. However, it is not a surprising event, as it has been reported previously that changes in the expression of genes at a low level may not be sensitive for microarray detection [2]. It has been observed in research studies that a very limited number of genes are regulated after the usage of Entinostat. These are the genes which possess different functions and belong to different categories. Their functions include protein phosphorylation, degradation and modification. ENTINOSTAT AND GENE EXPRESSION: It could be possible that the changes represent a reaction to the cellular stress that has been induced by the molecules may remain uncertain. However, it is possible that the repeated cycles of HDAC and DNMT inhibition could develop a more consistent change in the expression of genes by means of the action on specific promoters. MORE RESEARCH NEEDED: It has been postulated in research studies that the more advanced studies of specific gene methylation and expressions by using sensitive platforms would be required in order to confirm or refute the significance of combined DNMT and HDAC inhibition via demethylation and de-repression of specific genes. ENTINOSTAT †HOW TO KNOW THE IMPACTS? It should be noted down that the overall effect of overlapping schedule of Entinostat on the expression of gene in AML or MDS is uncertain. Gene expression arrays have been used in order to know the impacts of combined usage of molecules on gene expression and in order to know the link with methylation. Dissimilar to the conventional molecules that are used for the AML, the DNMT inhibitors including Entinostat need various cycles [3]. The slow response makes the study of the molecular mechanisms challenging. It has been seen in studies that the normal cells starts appearing after repeated exposure of Entinostat in the bunch of cycles. In addition to that, if there are no normal cells, then still there could be significantly different mixture of cells that is obtained after these cycles and that does not resemble to the pre-exposure status. CONCLUSION: Since we don’t have specific evidences for the transcriptional response to the HDAC and DNMT inhibitors and their combined actions, we have to consider some other mechanisms in order to explain the response of these molecules. For instance it could be possible that they work on the apoptotic pathways, immune responses and cellular senescence in the neoplastic clones in order to destroy them [4, 5 and 6]. REFERENCES: 1. Gojo I, Jiemjit A, Trepel JB, et al. Phase 1 and pharmacologic study of MS-275, a histone deacetylase inhibitor, in adults with refractory and relapsed acute leukemias. Blood 2007;109(7):2781-2790 2. Suzuki H, Gabrielson E, Chen W, et al. A genomic screen for genes upregulated by demethylation and histone deacetylase inhibition in human colorectal cancer. Nat Genet 2002;31(2):141-149. 3. Silverman LR, McKenzie DR, Peterson BL, et al. Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B. J Clin Oncol 2006;24(24):3895-903. 4. De Smet C, De Backer O, Faraoni I, Lurquin C, Brasseur F, Boon T. The activation of human gene MAGE-1 in tumor cells is correlated with genome-wide demethylation. Proc Natl Acad Sci U S A 1996;93(14):7149-7153. 5. Sigalotti L, Altomonte M, Colizzi F, et al. 5-Aza-2â€-deoxycytidine (decitabine) treatment of hematopoietic malignancies: a multimechanism therapeutic approach? Blood 2003;101(11):4644-4646. discussion: 4645â€4646. 6. Oki Y, Jelinek J, Shen L, Kantarjian HM, Issa JP. Induction of hypomethylation and molecular response after decitabine therapy in patients with chronic myelomonocytic leukemia. Blood 2008;111(4):2382-2384.
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