4-(4-Chloro-2-methylphenoxy)-N-hydroxybutanamide (CMH) targets mRNA of the c-FLIP variants and induces apoptosis in MCF-7 human breast cancer cells.
4-(4-Chloro-2-methylphenoxy)-N-hydroxybutanamide (CMH) targets mRNA of the c-FLIP variants and induces apoptosis in MCF-7 human breast cancer cells.
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DOI：
10.1007/s11010-010-0477-7
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发表时间：
2010-09
影响因子：
4.3
通讯作者：
Safa, Ahmad R.
中科院分区：
文献类型：
--
作者：
Bijangi-Vishehsaraei, Khadijeh;Saadatzadeh, Mohammad Reza;Huang, Su;Murphy, Michael P.;Safa, Ahmad R.
关键词：
细胞 FLICE（FADD 样 IL-1β 转换酶）抑制蛋白 (c-FLIP) 是肿瘤坏死因子相关凋亡诱导配体 TRAIL 和人类恶性肿瘤耐药性的主要耐药因子。 c-FLIP 是 caspase-8 和 -10 的拮抗剂，可抑制细胞凋亡，并以长 (c-FLIPL) 和短 (c-FLIPS) 剪接形式表达。 c-FLIP 通常在各种人类癌症中过度表达，包括乳腺癌。多项研究表明，通过特定 siRNA 沉默 c-FLIP 可使癌细胞对 TRAIL 和抗癌药物敏感。然而，全身性使用siRNA作为治疗剂目前还不实用。为了减少或抑制 c-FLIP 表达，需要小分子来靶向 c-FLIP，而不抑制 caspase-8 和 -10。我们使用了 c-FLIP 的小分子抑制剂 4-(4-氯-2-甲基苯氧基)-N-羟基丁酰胺 (CMH)，结果表明，CMH（而非其无活性类似物）下调了 c-FLIPL 和 c-FLIPS mRNA 和蛋白质水平，导致聚（ADP-核糖）聚合酶（PARP）降解，降低细胞存活率，并诱导 MCF-7 乳腺癌细胞凋亡。这些结果表明，c-FLIP 是一种关键的细胞凋亡调节剂，可以作为小分子抑制剂的靶标，下调其表达，并作为针对乳腺癌细胞的有效靶向治疗。
Cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein (c-FLIP) is a major resistance factor for the tumor necrosis factor-related apoptosis-inducing ligand TRAIL and in drug resistance in human malignancies. c-FLIP is an antagonist of caspases-8 and -10, which inhibits apoptosis and is expressed as long (c-FLIPL) and short (c-FLIPS) splice forms. c-FLIP is often overexpressed in various human cancers, including breast cancer. Several studies have shown that silencing c-FLIP by specific siRNAs sensitizes cancer cells to TRAIL and anticancer agents. However, systemic use of siRNA as a therapeutic agent is not practical at present. In order to reduce or inhibit c-FLIP expression, small molecules are needed to allow targeting c-FLIP without inhibiting caspases-8 and -10. We used a small molecule inhibitor of c-FLIP, 4-(4-chloro-2-methylphenoxy)-N-hydroxybutanamide (CMH), and show that CMH, but not its inactive analog, downregulated c-FLIPL and c-FLIPS mRNA and protein levels, caused poly(ADP-ribose) polymerase (PARP) degradation, reduced cell survival, and induced apoptosis in MCF-7 breast cancer cells. These results revealed that c-FLIP is a critical apoptosis regulator that can serve as a target for small molecule inhibitors that downregulate its expression and serve as effective targeted therapeutics against breast cancer cells.
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DOI：
10.1186/1756-9966-28-24
发表时间：
2009-02-20
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
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发表时间：
2005-07-01
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