Characterization of New Potential Anticancer Drugs Designed To Overcome Glutathione Transferase Mediated Resistance
Characterization of New Potential Anticancer Drugs Designed To Overcome Glutathione Transferase Mediated Resistance
复制标题
DOI：
10.1021/mp2000692
复制
发表时间：
2011-09-01
影响因子：
4.9
通讯作者：
Morgenstern, Ralf
中科院分区：
文献类型：
--
作者：
Johansson, Katarina;Ito, Mika;Morgenstern, Ralf
抗癌药物耐药性仍然是癌症治疗的严重障碍。在这里，我们使用新策略来靶向微粒体谷胱甘肽转移酶 1 (MGST1) 和谷胱甘肽转移酶 pi (GSTP)，它们通常在肿瘤中过度表达，并赋予对多种细胞抑制药物的耐药性，包括顺铂和阿霉素 (DOX)。之前的研究表明，通过将顺铂与 GST 抑制剂 ethacrynic add 合成组合形成依他拉铂，胞质 GST 抑制得到改善，细胞对顺铂变得更加敏感。在这里，我们发现依沙拉铂很容易被细胞吸收，并且可以逆转 MGST1 过表达 MCF7 细胞的顺铂耐药性。克服 GST 介导的耐药性的第二种新颖策略是使用 GST 可释放的细胞抑制药物。在这里，我们合成了 DOX 的两种衍生物，2,4-二硝基苯磺酰阿霉素 (DNS-DOX) 和 4-单硝基苯磺酰阿霉素 (MNS-DOX)，并表明它们是 MGST1 和 GSTP（释放 DOX）的底物。 MGST1 过表达细胞对 DOX 具有抗性。 DNS-DOX 可以部分逆转耐药性。有趣的是，与对照细胞相比，反应性较低的 MNS-DOX 对过度表达 MGST1 的细胞的细胞毒性更大。看来，通过控制前药的反应性并由此控制DOX释放速率，可以实现对MGST1过表达细胞的选择性毒性。就 V79 细胞而言，DOX 耐药性与 GSTP 表达水平成正比。在这种情况下，DNS-DOX 不仅消除了耐药性，而且在克隆形成试验中还观察到 GSTP 依赖性的毒性显着增加。总之，在 GST 过表达的细胞中，可以克服 MGST1 和 GSTP 对细胞生长抑制药物的耐药性，并增强细胞毒性。
Resistance against anticancer drugs remains a serious obstacle in cancer treatment. Here we used novel strategies to target microsomal glutathione transferase 1 (MGST1) and glutathione transferase pi (GSTP) that are often overexpressed in tumors and confer resistance against a number of cytostatic drugs, including cisplatin and doxorubicin (DOX). By synthetically combining cisplatin with a GST inhibitor, ethacrynic add, to form ethacraplatin, it was previously shown that cytosolic GST inhibition was improved and that cells became more sensitive to cisplatin. Here we show that ethacraplatin is easily taken up by the cells and can reverse cisplatin resistance in MGST1 overexpressing MCF7 cells. A second and novel strategy to overcome GST mediated resistance involves using GST releasable cytostatic drugs. Here we synthesized two derivatives of DOX, 2,4-dinitrobenzenesulfonyl doxorubicin (DNS-DOX) and 4-mononitrobenzenesulfonyl doxorubicin (MNS-DOX) and showed that they are substrates for MGST1 and GSTP (releasing DOX). MGST1 overexpressing cells are resistant to DOX. The resistance is partially reversed by DNS-DOX Interestingly, the less reactive MNS-DOX was more cytotoxic to cells overexpressing MGST1 than control cells. It would appear that, by controlling the reactivity of the prodrug and thereby the DOX release rate, selective toxicity to MGST1 overexpressing cells can be achieved. In the case of V79 cells, DOX resistance proportional to GSTP expression levels was noted. In this case, not only was drug resistance eliminated by DNS-DOX but a striking GSTP-dependent increase in toxicity was observed in the clonogenic assay. In summary, MGST1 and GSTP resistance to cytostatic drugs can be overcome and cytotoxicity can be enhanced in GST overexpressing cells.