ROS and RNS induced apoptosis through p53 and iNOS mediated pathway by a dibasic hydroxamic acid molecule in leukemia cells
ROS and RNS induced apoptosis through p53 and iNOS mediated pathway by a dibasic hydroxamic acid molecule in leukemia cells
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DOI：
10.1016/j.ejps.2013.11.009
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发表时间：
2014-02-14
影响因子：
4.6
通讯作者：
Choudhuri, Soumitra Kumar
中科院分区：
文献类型：
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作者：
Banerjee, Kaushik;Ganguly, Avishek;Choudhuri, Soumitra Kumar
抗癌药物诱导癌细胞凋亡，并且还对正常细胞表现出不期望的毒性。因此，开发新的触发细胞凋亡并对正常细胞具有低毒性的药物是最重要的。异羟肟酸通过细胞凋亡抑制肿瘤细胞生长，但其潜在机制尚不清楚。oxayl his（N-phenyl）hydroxamic acid（OBPHA）通过产生ROS和NO诱导阿霉素耐药T淋巴细胞白血病CEM/ADR 5000细胞凋亡。目前的研究公开了OBPHA选择性地杀死癌细胞，而不管它们的耐药表型。我们还确定了OBPHA的晶体结构，以了解细胞凋亡的结构要求;研究表明，取代的异羟肟酸基团（-CO-NH-OH）的存在有利于可能通过自变性产生NO。沿着诱导caspase 3介导的内源性凋亡; OBPHA还激活p53依赖性信号级联并以时间依赖性方式下调HDAC 3表达，这可能是由于ROS和NO产生增加以及细胞GSH水平同时降低。因此，ROS和NO介导的下游信号传导对于OBPHA的抗癌作用是必需的。因此，具有结构相关药效团的OBPHA为开发新的ROS和RNS产生化学物质诱导p53依赖性细胞凋亡提供了重要的见解。(C)2013爱思唯尔有限公司版权所有。
Anticancer drugs induce apoptosis to cancer cells and also exhibit undesired toxicity to normal cells. Therefore development of novel agents triggering apoptosis and have low toxicity towards normal cells is most important. Hydroxamic acids suppress tumour cell growth through apoptosis but the underlying mechanism is poorly understood.Herein, we describe the apoptotic potential of a dibasic hydroxamic acid derivative, viz., oxayl his (N-phenyl) hydroxamic acid (OBPHA), which induces apoptosis through generation of both ROS and NO in doxorubicin resistant T-Iymphoblastic leukemia, CEM/ADR5000 cells. Present study discloses that OBPHA selectively kills cancerous cells irrespective of their drug resistant phenotype. We also determined the crystal structure of OBPHA to understand the structural requirements for apoptosis; the study reveals that the presence of substituted hydroxamic acid groups (-CO-NH-OH) favours the generation of NO possibly through auto degeneration. Along with the induction of caspase 3 mediated intrinsic apoptosis; OBPHA also activates p53 dependent signalling cascade and downregulates HDAC3 expression in a time dependent manner possibly due to increased ROS and NO production and simultaneous decrease in cellular GSH level. Thus ROS and NO mediated downstream signalling are essential for the anticancer effect of OBPHA. Therefore OBPHA, having a structurally relevant pharmacophore provides important insight into the development of new ROS and RNS generating chemicals inducing p53 dependent apoptosis. (C) 2013 Elsevier B.V. All rights reserved.