title: Determinants of sensitivity to DZNep induced apoptosis in multiple myeloma cells.
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. 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. 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 quantitative RT-PCR. Western-blot analysis indicated ALOX5 was highly expressed only in sensitive cell line H929 and greatly decreased upon DZNep treatment. Ectopic expression of ALOX5 reduced sensitivity to DZNep in H929 cells. Furthermore, down-regulation of ALOX5 by RNA interference could also induce apoptosis in H929. Gene expression analysis on MM patient dataset indicated ALOX5 expression was significantly higher in MM patients compared to normal plasma cells. We also found that Bcl-2 was overexpressed in DZNep insensitive cells, and cotreatment with DZNep and ABT-737, a Bcl-2 family inhibitor, synergistically inhibited growth and induced apoptosis of DZNep insensitive MM cells. Taken together, this study shows one of mechanisms of the DZNep efficacy on MM correlates with its ability to down-regulate the ALOX5 levels. In addition, DZNep insensitivity might be associated with overexpression of Bcl-2, and the combination of ABT-737 and DZNep could synergistically induced apoptosis. These results suggest that DZNep may be exploited therapeutically for a subset of MM.
authors: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors: Zhigang
authors: Z
authors: Xie
authors: Chonglei
authors: C
authors: Bi
authors: Lip Lee
authors: LL
authors: Cheong
authors: Shaw Cheng
authors: SC
authors: Liu
authors: Gaofeng
authors: G
authors: Huang
authors: Jianbiao
authors: J
authors: Zhou
authors: Qiang
authors: Q
authors: Yu
authors: Chien-Shing
authors: CS
authors: Chen
authors: Wee Joo
authors: WJ
authors: Chng
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics / Q000378:metabolism; D001713:Biphenyl Compounds / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D000071221:Enhancer of Zeste Homolog 2 Protein; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009101:Multiple Myeloma / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D009596:Nitrophenols / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D063151:Polycomb Repressive Complex 2; D013449:Sulfonamides / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C501332:ABT-737; D001713:Biphenyl Compounds; D004268:DNA-Binding Proteins; D009596:Nitrophenols; D010879:Piperazines; D013449:Sulfonamides; D014157:Transcription Factors; C048460:3-deazaneplanocin; D001094:Arachidonate 5-Lipoxygenase; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D020169:Caspases; D000241:Adenosine