Organopalladium compound 7b targets mitochondrial thiols and induces caspase-dependent apoptosis in human myeloid leukemia cells.
Organopalladium compound 7b targets mitochondrial thiols and induces caspase-dependent apoptosis in human myeloid leukemia cells.
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DOI：
10.1038/cddis.2013.190
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发表时间：
2013-06-06
影响因子：
9
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中科院分区：
文献类型：
--
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近年来，慢性粒细胞白血病(CML)的治疗进展也伴随着肿瘤细胞逃避策略的发展，导致一些患者产生化疗耐药。由N，N-二甲基-1-苯乙胺(DMPA)与[1，2-乙烷双(二苯基膦)](Dppe)反应得到的专利有机钯化合物在体内和体外对黑色素瘤细胞具有很强的抗肿瘤活性。结果表明，环钯衍生物[Pd2(R(+))C2，N-DMPA)2(μ-dppe)Cl2]对K562人白血病细胞具有促进细胞死亡的作用，并对其作用机制进行了探讨。结果表明，化合物7b可通过释放细胞色素c和激活caspase3特异性地促进K562细胞的凋亡。在正常外周血单核细胞中未观察到这种细胞毒作用。化合物7b诱导的内源性细胞凋亡途径是由蛋白质硫醇氧化导致线粒体跨膜电位的耗散而触发的。二硫苏糖醇对化合物7b诱导的细胞死亡以及与细胞凋亡相关的所有下游事件的预防作用证实了死亡信号是由硫醇氧化引起的。这些发现有助于阐明Palladaccle 7b诱导细胞死亡的机制，并为该化合物在CML抗肿瘤化疗中的应用提供了一种有前景的药物。
The advances in the treatment of chronic myeloid leukemia (CML) during the last years were also accompanied by the development of evading strategies by tumor cells, resulting in chemotherapy resistance in some patients. Patented organopalladium compounds derived from the reaction of N,N-dimethyl-1-phenethylamine (dmpa) with [1,2-ethanebis(diphenylphosphine)] (dppe) exhibited a potent antitumor activity in vivo and in vitro in melanoma cells. We showed here that the cyclopalladated derivative [Pd2(R(+))C2, N-dmpa)2(μ-dppe)Cl2], named compound 7b, was highly effective to promote cell death in the K562 human leukemia cells and its mechanisms of action were investigated. It was shown that compound 7b was able to promote exclusively apoptotic cell death in K562 cells associated to cytochrome c release and caspase 3 activation. This cytotoxic effect was not observed in normal peripheral mononuclear blood cells. The compound 7b-induced intrinsic apoptotic pathway was triggered by the protein thiol oxidation that resulted in the dissipation of the mitochondrial transmembrane potential. The preventive effect of the dithiothreitol on the compound 7b-induced cell death and all downstream events associated to apoptosis confirmed that death signal was elicited by the thiol oxidation. These findings contribute to the elucidation of the palladacycle 7b-induced cell death mechanism and present this compound as a promising drug in the CML antitumor chemotherapy.
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影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Thun, Michael J.
通讯作者：
Thun, Michael J.
影响因子：
11.4
作者：
Friesen, C;Fulda, S;Debatin, KM
通讯作者：
Debatin, KM
影响因子：
5
作者：
Barbosa, Christiano M. V.;Oliveira, Carlos R.;Caires, Antonio C. F.
通讯作者：
Caires, Antonio C. F.
影响因子：
5.1
作者：
Oliveira, Carlos R.;Barbosa, Christiano M. V.;Bincoletto, Claudia
通讯作者：
Bincoletto, Claudia
影响因子：
2.9
作者：
HISSIN, PJ;HILF, R
通讯作者：
HILF, R