Diaz Z, Mann K K, Marcoux S, Kourelis M, Colombo M, Komarnitsky P B, Miller W H
Department of Oncology, Segal Cancer Comprehensive Center, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montréal, Quebec, Canada.
Leukemia. 2008 Oct;22(10):1853-63. doi: 10.1038/leu.2008.194. Epub 2008 Jul 17.
Inorganic arsenic trioxide (As(2)O(3)) is a highly effective treatment for acute promyelocytic leukemia (APL). However, other cancers do not respond well to this form of arsenic at clinically achievable doses. We tested a novel arsenical, S-dimethylarsino-glutathione (darinaparsin) for efficacy in various malignancies in vitro. Darinaparsin is significantly more potent than As(2)O(3) at mediating apoptosis in various malignant cell lines and is highly active against APL cells derived for As(2)O(3) resistance. We provide evidence that darinaparsin triggers apoptosis by inducing signaling pathways that do not completely overlap with As(2)O(3). We show that darinaparsin induces apoptosis and oxidative stress to a greater extent than As(2)O(3), although like As(2)O(3), darinaparsin-induced toxicity is c-Jun NH(2)-terminal kinase-dependent. However, darinaparsin does not induce promyelocytic leukemia/retinoic acid receptor alpha (PML/RAR alpha) degradation or rearrange PML nuclear bodies in APL cells, nor is its toxicity increased by glutathione depletion. Darinaparsin treatment results in higher intracellular arsenic accumulation when compared to As(2)O(3) treatment. This may be explained by our finding that As(2)O(3), but not darinaparsin, is efficiently exported by ABCC1, suggesting increased therapeutic efficacy of darinaparsin in ABCC1-overexpressing tumors. Our studies indicate that darinaparsin efficiently kills tumor cells with increased antioxidant capacity and drug exporters and suggest that darinaparsin may have a broader therapeutic spectrum than As(2)O(3).
无机三氧化二砷（As₂O₃）是治疗急性早幼粒细胞白血病（APL）的一种高效药物。然而，在临床可达到的剂量下，其他癌症对这种形式的砷反应不佳。我们测试了一种新型砷化合物S - 二甲基砷基谷胱甘肽（达里纳帕辛）在体外对各种恶性肿瘤的疗效。达里纳帕辛在介导各种恶性细胞系凋亡方面比As₂O₃显著更有效，并且对源自As₂O₃耐药的APL细胞具有高度活性。我们提供的证据表明，达里纳帕辛通过诱导与As₂O₃不完全重叠的信号通路触发凋亡。我们表明，达里纳帕辛比As₂O₃更能诱导凋亡和氧化应激，尽管与As₂O₃一样，达里纳帕辛诱导的毒性依赖于c - Jun NH₂ - 末端激酶。然而，达里纳帕辛不会诱导APL细胞中早幼粒细胞白血病/维甲酸受体α（PML/RARα）降解或重排PML核体，其毒性也不会因谷胱甘肽耗竭而增加。与As₂O₃处理相比，达里纳帕辛处理导致细胞内砷积累更高。这可能由我们的发现来解释，即As₂O₃可被ABCC1有效转运，而达里纳帕辛则不能，这表明达里纳帕辛在ABCC1过表达的肿瘤中具有更高的治疗效果。我们的研究表明，达里纳帕辛能有效杀死抗氧化能力增强和有药物转运蛋白的肿瘤细胞，并表明达里纳帕辛可能比As₂O₃具有更广泛的治疗谱。
