Institute of Environmental Medicine, Karolinska Institutet, SE-17177 Stockholm, Sweden.
Mol Pharm. 2011 Oct 3;8(5):1698-708. doi: 10.1021/mp2000692. Epub 2011 Aug 30.
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 acid, 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.
抗癌药物耐药性仍然是癌症治疗中的一个严重障碍。在这里，我们使用新的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），这些酶在肿瘤中经常过度表达，并赋予对多种细胞抑制剂的耐药性，包括顺铂和阿霉素（DOX）。通过将顺铂与 GST 抑制剂乙叉二醛酸合成，形成乙叉铂，先前表明细胞溶质 GST 抑制得到改善，细胞对顺铂变得更加敏感。在这里，我们表明乙叉铂很容易被细胞摄取，并可以逆转 MGST1 过表达的 MCF7 细胞中的顺铂耐药性。克服 GST 介导的耐药性的第二种新策略涉及使用 GST 释放的细胞抑制剂。在这里，我们合成了 DOX 的两种衍生物，2,4-二硝基苯磺酰基阿霉素（DNS-DOX）和 4-单硝基苯磺酰基阿霉素（MNS-DOX），并表明它们是 MGST1 和 GSTP 的底物（释放 DOX）。 MGST1 过表达的细胞对 DOX 具有抗性。DNS-DOX 部分逆转了这种耐药性。有趣的是，反应性较低的 MNS-DOX 对过表达 MGST1 的细胞比对照细胞更具细胞毒性。似乎通过控制前药的反应性，从而控制 DOX 释放率，可以实现对 MGST1 过表达细胞的选择性毒性。在 V79 细胞中，观察到与 GSTP 表达水平成正比的 DOX 耐药性。在这种情况下，不仅通过 DNS-DOX 消除了药物耐药性，而且在集落形成测定中观察到 GSTP 依赖性毒性显着增加。总之，可以克服 MGST1 和 GSTP 对细胞抑制剂的耐药性，并可以增强 GST 过表达细胞的细胞毒性。
