M344

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Background

M344 is a potent inhibitor of HDAC with IC50 value of 100 nM and enable the induction of cell differentiation [1]. Treatment with M344 for 1 or 3 days induced a decreased relative p53 mRNA level and increased p21waf1/cip1 mRNA expression while no change in p53 protein. The result demonstrated the independent of p53 of inhibitory effects of M344 on MCF-7 cell growth. And the increased expression of the pro-apoptotic Puma, which can be induced by p53-independent pathways, is in accordance with the suppression of MCF-7 cell growth observed after the M344 treatment. On the other hand, M344 also show the ability in increasing the response to radiation in SCC-35 and SQ-20B human squamous carcinoma lines [2]. In MEL DS19 cells, M344 shows a much more significant effect on cell proliferation than the effect on cell differentiation. M344 exhibits toxic at concentrations of above 10 μM, when only 20% of the surviving cell population at most are induced to differentiate. M344 significantly inhibits proliferation of embryonic nervous system tumor cells, including medulloblastoma cells (D341 MED) with GI50 value of 0.65 μM and neuroblastoma cells (CH-LA 90) with GI50 value of 0.63 μM [1, 3]. M344 also plays an important role in the modification of histone and transcription factor of NF- kB in regulating HIV-1 LTR gene expression, showing the potential anti-latency therapies. Experiments were carried out in the cells, which latently infected Jurkat cells encoding the green fluorescence protein (GFP) under control of the HIV-1 LTR that act as a marker of expression of HIV-1 LTR, 72 hours after treatment with 200 nM M344, expression of HIV-1 activity was found, and the percentage of GFP-expressing cells was detected as high as 25.2% more than the cells which was subjected to mock treatment [4].

[1]. Jung M, Brosch G , Kolle D, et al. Amide analogues of trichostatin A as inhibitors of histone deacetylase and inducers of terminal cell differentiation. JOURNAL OF MEDICINAL CHEMISTRY, 1999, 42 (22): 4669-4679.
[2]. Yeung A, Bhargava RK, Ahn, R, et al. HDAC inhibitor M344 suppresses MCF-7 breast cancer cell proliferation. BIOMEDICINE & PHARMACOTHERAPY, 2012, 66 (3): 232-236.
[3]. Furchert SE, Lanvers-Kaminsky C , Jurgens H , et al. Inhibitors of histone deacetylases as potential therapeutic tools for high-risk embryonal tumors of the nervous system of childhood. INTERNATIONAL JOURNAL OF CANCER, 2007, 120 (8): 1787-1794.
[4]. Ying H, Zhang YH , Zhou X , et al. Selective Histonedeacetylase Inhibitor M344 Intervenes in HIV-1 Latency through Increasing Histone Acetylation and Activation of NF-kappaB. PLOS ONE, 2012, 7 (11): e48832.