Targeting poly (ADP-ribose) polymerase partially contributes to bufalin-induced cell death in multiple myeloma cells.
Targeting poly (ADP-ribose) polymerase partially contributes to bufalin-induced cell death in multiple myeloma cells.
复制标题
靶向多聚（ADP-核糖）聚合酶部分促进蟾蜍灵诱导的多发性骨髓瘤细胞细胞死亡
DOI：
10.1371/journal.pone.0066130
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Wu YL
中科院分区：
文献类型：
--
作者：
Huang H;Cao Y;Wei W;Liu W;Lu SY;Chen YB;Wang Y;Yan H;Wu YL
尽管最近在治疗药物方面取得了进展，但多发性骨髓瘤（MM）仍然是一种无法治愈的疾病。最近，聚（ADP-核糖）聚合酶1（PARP 1）已被证明是MM治疗的潜在有前途的靶点。先前的一份报告表明，蟾毒灵，一种传统中药（“蟾酥”）的成分，可能靶向PARP 1。然而，这一假设尚未得到证实。蟾蜍灵在体外能抑制PARP 1的活性，并能减少MM细胞中DNA损伤诱导的聚腺苷二磷酸核糖基化。分子对接分析表明蟾毒灵相互作用的活性位点在PAPR 1的催化结构域内。因此，PARP 1是蟾蜍灵的假定靶点。此外，我们首次发现蟾毒灵可抑制MM细胞系（NCI-H929，U266，RPMI 8226和MM. 1 S）和原代CD 138 + MM细胞的增殖，主要通过凋亡和G2-M期细胞周期阻滞。MM细胞凋亡通过凋亡细胞形态学、Annexin-V阳性细胞和caspase 3活化来证实。我们进一步评估了PARP 1在蟾蜍灵诱导的细胞凋亡中的作用，发现PARP 1过表达部分抑制蟾蜍灵诱导的细胞死亡。蟾蜍灵可作为化疗增敏剂，增强拓扑替康、喜树碱、依托泊苷和伏立诺他对MM细胞的生长抑制作用。总的来说，我们的数据表明蟾毒灵是一种新的PARP 1抑制剂，是一种潜在的有前途的治疗药物，单独或与其他药物联合治疗MM。
Despite recent pharmaceutical advancements in therapeutic drugs, multiple myeloma (MM) remains an incurable disease. Recently, ploy(ADP-ribose) polymerase 1 (PARP1) has been shown as a potentially promising target for MM therapy. A previous report suggested bufalin, a component of traditional Chinese medicine (“Chan Su”), might target PARP1. However, this hypothesis has not been verified. We here showed that bufalin could inhibit PARP1 activity in vitro and reduce DNA–damage-induced poly(ADP-ribosyl)ation in MM cells. Molecular docking analysis revealed that the active site of bufalin interaction is within the catalytic domain of PAPR1. Thus, PARP1 is a putative target of bufalin. Furthermore, we showed, for the first time that the proliferation of MM cell lines (NCI-H929, U266, RPMI8226 and MM.1S) and primary CD138+ MM cells could be inhibited by bufalin, mainly via apoptosis and G2-M phase cell cycle arrest. MM cell apoptosis was confirmed by apoptotic cell morphology, Annexin-V positive cells, and the caspase3 activation. We further evaluated the role of PARP1 in bufalin-induced apoptosis, discovering that PARP1 overexpression partially suppressed bufalin-induced cell death. Moreover, bufalin can act as chemosensitizer to enhance the cell growth-inhibitory effects of topotecan, camptothecin, etoposide and vorinostat in MM cells. Collectively, our data suggest that bufalin is a novel PARP1 inhibitor and a potentially promising therapeutic agent against MM alone or in combination with other drugs.
登录
查看更多内容
影响因子：
46.9
作者：
通讯作者：
--
影响因子：
16
作者：
Krishnakumar R;Kraus WL
通讯作者：
Kraus WL
影响因子：
4.6
作者：
Premkumar, Daniel R.;Jane, Esther P.;Agostino, Naomi R.;DiDomenico, Joseph D.;Pollack, Ian F.
通讯作者：
Pollack, Ian F.
影响因子：
6.2
作者：
Meng, Zhiqiang;Yang, Peiying;Shen, Yehua;Bei, Wenying;Zhang, Ying;Ge, Yongqian;Newman, Robert A.;Cohen, Lorenzo;Liu, Luming;Thornton, Bob;Chang, David Z.;Liao, Zongxing;Kurzrock, Razelle
通讯作者：
Kurzrock, Razelle
影响因子：
20.3
作者：
Neri, Paola;Ren, Li;Bahlis, Nizar J.
通讯作者：
Bahlis, Nizar J.