Singh Gaganmeet, Dey Chinmoy S
Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER), Punjab, India.
Acta Trop. 2007 Sep;103(3):172-85. doi: 10.1016/j.actatropica.2007.06.004. Epub 2007 Jun 16.
The current study has been undertaken to investigate the sensitivity of the topoisomerase II (topo II) of wild type (Ld-Wt) and arsenite-resistant (Ld-As20) L. donovani to an anti-leishmanial agent pentamidine and an anti-cancer drug doxorubicin. We demonstrate that the cross resistance to pentamidine and doxorubicin in Ld-As20, was in part implicated through differential inhibition of topo II in Ld-Wt and Ld-As20. Further, the treatment of promastigotes at drug concentrations inhibiting 50% of topo II activity inflicted a regulated cell death sharing several apoptotic features like externalization of phosphatidylserine, loss of mitochondrial membrane potential, cytochrome C release into the cytosol, activation of cellular proteases and DNA fragmentation. The cytotoxic potential of pentamidine and doxorubicin in L. donovani has been shown to be mediated through topoisomerase II inhibition and results in inciting programmed cell death process.
本研究旨在调查野生型（Ld-Wt）和抗亚砷酸盐（Ld-As20）的杜氏利什曼原虫的拓扑异构酶II（topo II）对抗利什曼原虫药物喷他脒和抗癌药物阿霉素的敏感性。我们证明，Ld-As20对喷他脒和阿霉素的交叉耐药性部分是由于Ld-Wt和Ld-As20中topo II的差异抑制所致。此外，用抑制50% topo II活性的药物浓度处理前鞭毛体，会导致一种程序性细胞死亡，其具有若干凋亡特征，如磷脂酰丝氨酸外化、线粒体膜电位丧失、细胞色素C释放到细胞质中、细胞蛋白酶激活和DNA片段化。已表明喷他脒和阿霉素在杜氏利什曼原虫中的细胞毒性潜力是通过拓扑异构酶II抑制介导的，并导致程序性细胞死亡过程的激发。
