Arsenic compounds induce cytotoxicity and apoptosis in cisplatin-sensitive and -resistant gynecological cancer cell lines
Arsenic compounds induce cytotoxicity and apoptosis in cisplatin-sensitive and -resistant gynecological cancer cell lines
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DOI：
10.1007/s002800100278
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发表时间：
2001-06-01
影响因子：
3
通讯作者：
Ho, PC
中科院分区：
文献类型：
--
作者：
Du, YH;Ho, PC
目的：砷化合物通过下调bcl-2的表达，可有效治疗急性早幼粒细胞白血病。耐药卵巢癌细胞通常过度表达bcl-2或p53蛋白，或两者都表达。我们假设砷化合物，如As2O3和as (2)S(3)也可能对传统化疗耐药的妇科癌症有活性。方法：在体外研究这两种砷化合物对顺铂（CDDP）敏感（OVCAR、CG、JAM）和耐药（C180-13S）的卵巢癌细胞株和对人宫颈癌细胞株（HeLa）的影响，并比较其对人成纤维细胞（HF）的影响。基于测量细胞中荧光素二醋酸酯（FDA）的荧光测定法用于确定细胞活力。细胞凋亡是通过流式细胞术和DNA片段分析来评估的。结果：用As2O3或As2S3处理每个细胞系导致细胞生长明显的剂量依赖性下降。这两种化合物的IC50表明对所有癌细胞的细胞毒性作用明显大于对正常HF的细胞毒性作用。在临床可达到的浓度（2mum）下，AS(2)O(3)选择性抑制C180-13S、OVCAR和HeLa细胞的生长和诱导凋亡，但对GO、JAM细胞和HF无明显凋亡作用，5mum As2S3处理后，C180-13S、OVCAR和HeLa细胞也表现出生长抑制和诱导凋亡的作用。结论：砷化合物（As2O3和As2S3）可在临床可达到的浓度下抑制卵巢癌和宫颈癌细胞的生长并诱导细胞凋亡，提示As2O3和As2S3可有效治疗妇科肿瘤。
Purpose: Arsenic compounds have been found to be effective in the treatment of acute promyelocytic leukemia through the downregulation of bcl-2 expression. Resistant ovarian cancer cells often overexpress bcl-2 or p53 proteins or both. We hypothesized that arsenic compounds, such as As2O3 and AS(2)S(3) could also be active against gynecological cancers resistant to conventional chemotherapy. Methods: We investigated the effects of these two arsenic compounds in vitro on ovarian cancer cell lines sensitive (OVCAR, CG, JAM) and resistant (C180-13S) to cisplatin (CDDP) and on human cervical cancer cell lines (HeLa) in comparison with their effects on human fibroblasts (HF). A fluorometric assay based on measurements of fluorescein diacetate (FDA) in cells was used to determine cell viability. Apoptosis was assessed in terms of cell morphology, by flow cytometry and by a DNA fragmentation assay. Results: Treatment of each cell line with the As2O3 or As2S3 led to a marked dose-dependent decrease in cell growth. The IC50 of the two compounds indicated a significantly greater cytotoxic effect against all the cancer cells tested than against the normal HF. At a clinically achievable concentration (2 muM), AS(2)O(3) selectively inhibited the growth and induced apoptosis in C180-13S, OVCAR and HeLa cells but had no significant apoptotic effect on GO or JAM cells or HF, Following treatment with 5 muM As2S3, the C180-13S, OVCAR and HeLa cells also exhibited growth inhibition and induction of apoptosis. Conclusions: Arsenic compounds (As2O3 and As2S3) call inhibit growth and induce apoptosis in human ovarian and cervical cancer cells at clinically achievable concentrations, indicating that As2O3 and As2S3 could be effective in the treatment of gynecological cancer.