HZ08, a great regulator to reverse multidrug resistance via cycle arrest and apoptosis sensitization in MCF-7/ADM
HZ08, a great regulator to reverse multidrug resistance via cycle arrest and apoptosis sensitization in MCF-7/ADM
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DOI：
10.1016/j.ejphar.2010.08.013
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发表时间：
2010-11-25
影响因子：
5
通讯作者：
Huang, Wen-long
中科院分区：
文献类型：
--
作者：
Cen, Juan;Qi, Yan;Huang, Wen-long
在早期研究中，证明R-HZ 08、S-HZ 08和外消旋体在体外和体内具有强的多药耐药性逆转功效（Yan等人，2008年b）。这种作用可能与MCF-7/ADM中的多药耐药相关蛋白（MRP 1）和K562/A02中的P-糖蛋白直接相互作用。我们的最新研究发现HZ 08可通过协同作用促进化疗诱导的细胞凋亡，其作用机制包括活性氧生成、GSH耗竭、线粒体膜电位去极化、细胞色素c释放和caspase激活。此外，HZ 08对耐药细胞的潜在选择性作用表明HZ 08具有通过凋亡调节逆转耐药的特异性靶点。因此，我们追踪了HZ 08的个体影响，不仅对凋亡途径本身，而且对凋亡相关的细胞内调节系统。HZ 08可使MCF-7/ADM细胞的G（0）/G（1）期细胞数增加，并可调节凋亡相关蛋白Bcl-2、Bax和上游功能分子c-Myc、c-Fos，从而促进化疗诱导的MCF-7/ADM细胞凋亡。R-HZ 08在上述大部分靶点上的效果均优于S-HZ 08或外消旋体。HZ 08对细胞内Ca ~（2+）浓度无明显影响，无维拉帕米的副作用。考虑到多药耐药是多因素的，HZ 08，尤其是R-HZ 08，可通过多重改善肿瘤细胞的上游恶性特性，使细胞凋亡敏感化，有望成为提高多药耐药肿瘤化疗效果的药物。(c)2010 Elsevier B. V.保留所有权利。
In early studies, it was demonstrated that R-HZ08, S-HZ08 and the racemate had strong reverse efficacy of multidrug resistance in vitro and in vivo (Yan et al., 2008b). The effect was supposed to have direct interaction with multidrug resistance-associated protein (MRP1) in MCF-7/ADM and P-glycoprotein in K562/A02. According to our latest study, we found HZ08 could enhance chemotherapy induced apoptosis by synergistic action on reactive oxygen species generation, GSH depletion, mitochondrial membrane potential depolarization, cytochrome c release and caspase activation. Moreover, the potential selective effect of HZ08 on resistant cells suggested that HZ08 have specific targets for resistance reversal via apoptosis regulation. Therefore, we traced individual influence of HZ08, not only on apoptosis pathway per se but also on apoptosis related intracellular regulation systems. Then we found HZ08 could increase cells in G(0)/G(1) phase and regulate apoptosis related proteins (Bcl-2, Bax) as well as upstream functional molecules (c-Myc and c-Fos), which are usually abnormal in malignancy and responsible for multidrug resistance in MCF-7/ADM. Thereby, chemotherapy induced apoptosis was promoted. R-HZ08 showed better effect than S-HZ08 or the racemate did in most of targets above. Furthermore, HZ08 did not change the concentration of intracellular Ca2+ which means it would not have side effect as verapamil does. Considering multidrug resistance is multifactorial, HZ08, especially R-HZ08, which could sensitize apoptosis by multiple improvements of upstream malignant characters, will be a promising drug to enhance the effect of chemotherapy in the treatment of multidrug resistant tumor. (c) 2010 Elsevier B.V. All rights reserved.