The alkaloid sanguinarine is effective against multidrug resistance in human cervical cells via bimodal cell death
The alkaloid sanguinarine is effective against multidrug resistance in human cervical cells via bimodal cell death
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DOI：
10.1016/s0006-2952(02)00902-4
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发表时间：
2002-04-15
影响因子：
5.8
通讯作者：
Liepins, A
中科院分区：
文献类型：
--
作者：
Ding, ZH;Tang, SC;Liepins, A
血根碱是一种苯并蒽碱生物碱，通过诱导细胞死亡途径具有潜在的抗肿瘤作用。多药耐药（MDR）的发展是化疗药物取得成功的主要障碍。本研究的目的是调查血碱是否有效对抗宫颈耐多药，如果有效，通过何种机制。比较了血根碱对人乳头瘤病毒（HPV） 16型永生化宫颈细胞及其耐多药对应物细胞的影响。台盼蓝排除试验和克隆存活试验表明，耐多药人宫颈细胞对血碱诱导的死亡和对药物敏感的亲本细胞一样敏感。在用血根碱处理两种类型的细胞后，观察到两种不同的浓度依赖的细胞死亡模式。用2.12或4.24 muM血碱处理后，大多数细胞死亡，通过光镜和扫描电镜检测细胞表面起泡，Western blot检测caspase-3的蛋白水解激活和caspase-3底物聚（adp -核糖）聚合酶（PARP）的裂解，结果显示细胞凋亡。然而，8.48和16.96 muM sanguinarine引起第二种细胞死亡模式，即肿瘤，以细胞表面起泡为特征，既没有caspase-3激活，也没有PARP切割。本研究首次提供证据表明，血根碱通过双峰细胞死亡对多药耐药宫颈细胞有效，双峰细胞死亡显示了涉及不同形态和caspase-3激活状态的可选择机制。(C) 2002爱思唯尔科学有限公司版权所有。
Sanguinarine, a benzophenanthrine alkaloid, is potentially antineoplastic through induction of cell death pathways. The development of multidrug resistance (MDR) is a major obstacle to the success of chemotherapeutic agents. The aim of this study was to investigate whether sanguinarine is effective against uterine cervical MDR and, if so, by which mechanism. The effects of treatment with sanguinarine on human papillomavirus (HPV) type 16-immortalized endocervical cells and their MDR counterpart cells were compared. Trypan blue exclusion assays and clonogenic survival assays demonstrated that MDR human cervical cells are as sensitive as their drug-sensitive parental cells to death induced by sanguinarine. Upon treatment of both types of cells with sanguinarine, two distinct concentration-dependent modes of cell death were observed. Treatment with 2.12 or 4.24 muM sanguinarine induced death in most cells that was characterized as apoptosis using the criteria of cell surface blebbing, as determined by light and scanning electron microscopy, and proteolytic activation of caspase-3 and cleavage of the caspase-3 substrate poly(ADP-ribose) polymerase (PARP), as detected by Western blot analysis. However, 8.48 and 16.96 muM sanguinarine caused a second mode of cell death, oncosis, distinguished by cell surface blistering, and neither caspase-3 activation nor PARP cleavage. This study provides the first evidence that sanguinarine is effective against MDR in cervical cells via bimodal cell death, which displays alternative mechanisms involving different morphologies and caspase-3 activation status. (C) 2002 Elsevier Science Inc. All rights reserved.