Abstract

Abstract The 3-Deazaneplanocin A (DZNep), one of S-adenosylhomocysteine (AdoHcy) hydrolase inhibitors, has shown antitumor activities in a broad range of solid tumors and acute myeloid leukemia. It was found that DZNep effectively depletes EZH2 levels and inhibits trimethylation of lysine 27 on histone H3. Here, we examined its effects on multiple myeloma (MM) cells and found that, at 500 nM, it potently inhibited growth and induced apoptosis in 2 of 8 MM cell lines(8226, H929, KMS11, KMS12BM, KMS18, MM1S, OPM-2 and U266). We then attempted to identify molecular mechanisms of sensitivity to DZNep. RNA from un-treated and DZNep treated cells was profiled by Affymetrix HG-U133 Plus 2.0 microarray and genes with a significant change in gene expression were determined by significance analysis of microarray (SAM) testing. ALOX5 was the most down-regulated gene (5.8-fold) in sensitive cells and was expressed at low level in resistant cells. The results were corroborated by qRT-PCR. Western-blot analysis indicated ALOX5 was highly expressed only in sensitive cell line H929 and greatly decreased upon DZNep treatment. Furthermore, down-regulation of ALOX5 by RNA interference can also induce apoptosis in H929. Since it was reported ALOX5 can regulate IL-6 mRNA level, we also determined IL-6 and IL-6R expression by qRT-PCR. As expected, IL-6 and IL-6R mRNA levels were decreased (>2-fold) in H929 upon DZNep treatment. May-Grunwald-Giemsa staining demonstrated that treatment with DZNep also dose dependently induced nuclear and cytoplasmic morphologic features of apoptosis in H929. These findings in vitro warrants further investigation of DZNep for the treatment of MM in vivo. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4526.

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