Glick R D, Swendeman S L, Coffey D C, Rifkind R A, Marks P A, Richon V M, La Quaglia M P
Department of Surgery, Sloan-Kettering Institute, and Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Cancer Res. 1999 Sep 1;59(17):4392-9.
Inhibitors of histone deacetylase (HDAC) have been shown to have both apoptotic and differentiating effects on various tumor cells. M-carboxycinnamic acid bishydroxamide (CBHA) is a recently developed hybrid polar compound structurally related to hexamethylene bisacetamide. CBHA is a potent inhibitor of HDAC activity. CBHA induces cellular growth arrest and differentiation in model tumor systems. We undertook an investigation of the effects of CBHA on human neuroblastoma cell lines in vitro. When added to cultures of a panel of neuroblastoma cell lines, CBHA induced the accumulation of acetylated histones H3 and H4, consistent with the inhibition of HDAC. Concentrations of CBHA between 0.5 microM and 4 microM led to apoptosis in nine of nine neuroblastoma cell lines. Apoptosis was assessed by DNA fragmentation analysis and the appearance of a sub-G1 (<2N ploidy) population by flow cytometric analysis. The addition of a caspase inhibitor (benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone) completely abrogated CBHA-induced apoptosis in three of three cell lines. The addition of cycloheximide greatly reduced CBHA-induced apoptosis, suggesting that apoptotic induction was dependent on de novo protein synthesis. In addition, CBHA induced the expression of both CD95 (APO-1/Fas) and CD95 ligand within 12 h. The effect of CBHA on human neuroblastoma cells suggests that this agent and structurally related synthetic hybrid polar compounds have therapeutic potential for the treatment of this malignancy.
组蛋白去乙酰化酶（HDAC）抑制剂已被证明对多种肿瘤细胞具有凋亡和分化作用。间羧基肉桂酸双羟肟酸（CBHA）是一种最近开发的杂化极性化合物，其结构与六亚甲基双乙酰胺相关。CBHA是HDAC活性的有效抑制剂。CBHA在模型肿瘤系统中诱导细胞生长停滞和分化。我们对CBHA在体外对人神经母细胞瘤细胞系的作用进行了研究。当将CBHA添加到一组神经母细胞瘤细胞系的培养物中时，它诱导了组蛋白H3和H4的乙酰化积累，这与HDAC的抑制作用一致。0.5微摩尔至4微摩尔浓度的CBHA导致九种神经母细胞瘤细胞系中的九种发生凋亡。通过DNA片段化分析和流式细胞术分析出现亚G1期（<2N倍体）群体来评估凋亡。添加半胱天冬酶抑制剂（苄氧羰基-Val-Ala-Asp-氟甲基酮）完全消除了三种细胞系中CBHA诱导的凋亡。添加放线菌酮大大降低了CBHA诱导的凋亡，表明凋亡诱导依赖于从头蛋白质合成。此外，CBHA在12小时内诱导了CD95（APO-1/Fas）和CD95配体的表达。CBHA对人神经母细胞瘤细胞的作用表明，这种药物和结构相关的合成杂化极性化合物对治疗这种恶性肿瘤具有治疗潜力。
