Sulindac sulfide selectively increases sensitivity of ABCC1 expressing tumor cells to doxorubicin and glutathione depletion.
Sulindac sulfide selectively increases sensitivity of ABCC1 expressing tumor cells to doxorubicin and glutathione depletion.
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DOI：
10.7555/jbr.30.20150108
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发表时间：
2016-03
影响因子：
2.3
通讯作者：
Piazza GA
中科院分区：
文献类型：
--
作者：
Whitt JD;Keeton AB;Gary BD;Sklar LA;Sodani K;Chen ZS;Piazza GA
ATP结合盒（ABC）转运体ABCC 1（MRP 1）、ABCB 1（P-gp）和ABCG 2（BCRP）导致化疗失败。本研究的主要目的是描述非甾体抗炎药（NSAID）舒林酸硫化物逆转ABCC 1介导的化疗药物耐药性的疗效和机制，并确定舒林酸硫化物是否可以影响化疗药物的敏感性，而不依赖于药物外排。进行细胞毒性测定以测量ABC表达细胞系对阿霉素和其他化疗药物的抗性。测试了NSAID恢复对选定肿瘤细胞系以及一大组标准肿瘤细胞系的抗性的敏感性的能力。其他实验表征了舒林酸硫化物在分离的膜囊泡和完整细胞中抑制ABCC 1底物和共底物（GSH）转运的机制。多药耐药（MDR）的选择性逆转，减少流出的阿霉素，荧光底物证明了舒林酸硫化物和相关的NSAID，吲哚美辛，在耐药选择和工程细胞系表达ABCC 1，但不ABCB 1或ABCG 2。舒林酸硫化物也抑制了白三烯C4进入膜囊泡的转运。舒林酸硫化物增强了47种肿瘤细胞系中的24种对阿霉素的敏感性，包括所有测试的黑素瘤细胞系（7-7）。舒林酸硫化物还降低ABCC 1表达细胞中的胞内GSH，而谷胱甘肽合成抑制剂BSO选择性地增加对舒林酸硫化物诱导的细胞毒性的敏感性。在临床可达到的浓度下，舒林酸硫化物有效地和选择性地逆转ABCC 1介导的MDR。表达ABCC 1的肿瘤可能对舒林酸硫化物的直接细胞毒性以及与诱导氧化应激的化疗药物的组合高度敏感。
ATP-binding cassette (ABC) transpo rters ABCC1 (MRP1), ABCB1 (P-gp), and ABCG2 (BCRP) contribute to chemotherapy failure. The primary goals of this study were to characterize the efficacy and mechanism of the nonsteroidal anti-inflammatory drug (NSAID), sulindac sulfide, to reverse ABCC1 mediated resistance to chemotherapeutic drugs and to determine if sulindac sulfide can influence sensitivity to chemotherapeutic drugs independently of drug efflux. Cytotoxicity assays were performed to measure resistance of ABC-expressing cell lines to doxorubicin and other chemotherapeutic drugs. NSAIDs were tested for the ability to restore sensitivity to resistance selected tumor cell lines, as well as a large panel of standard tumor cell lines. Other experiments characterized the mechanism by which sulindac sulfide inhibits ABCC1 substrate and co-substrate (GSH) transport in isolated membrane vesicles and intact cells. Selective reversal of multi-drug resistance (MDR), decreased efflux of doxorubicin, and fluorescent substrates were demonstrated by sulindac sulfide and a related NSAID, indomethacin, in resistance selected and engineered cell lines expressing ABCC1, but not ABCB1 or ABCG2. Sulindac sulfide also inhibited transport of leukotriene C4 into membrane vesicles. Sulindac sulfide enhanced the sensitivity to doxorubicin in 24 of 47 tumor cell lines, including all melanoma lines tested (7-7). Sulindac sulfide also decreased intracellular GSH in ABCC1 expressing cells, while the glutathione synthesis inhibitor, BSO, selectively increased sensitivity to sulindac sulfide induced cytotoxicity. Sulindac sulfide potently and selectively reverses ABCC1-mediated MDR at clinically achievable concentrations. ABCC1 expressing tumors may be highly sensitive to the direct cytotoxicity of sulindac sulfide, and in combination with chemotherapeutic drugs that induce oxidative stress.