Characterization of New Potential Anticancer Drugs Designed To Overcome Glutathione Transferase Mediated Resistance

• Published in: Molecular pharmaceutics Vol. 8; no. 5; pp. 1698 - 1708
• Main Authors: Johansson, Katarina, Ito, Mika, Schophuizen, Carolien M. S, Mathew Thengumtharayil, Sherin, Heuser, Vanina D, Zhang, Jie, Shimoji, Miyuki, Vahter, Marie, Ang, Wee Han, Dyson, Paul J, Shibata, Aya, Shuto, Satoshi, Ito, Yoshihiro, Abe, Hiroshi, Morgenstern, Ralf
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 03.10.2011
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Breast Neoplasms - drug therapy; Breast Neoplasms - enzymology; Breast Neoplasms - metabolism; Cell Line; Cell Line, Tumor; Cisplatin - analogs & derivatives; Cisplatin - metabolism; Cisplatin - pharmacology; Cricetinae; Cricetulus; Cytostatic Agents - chemistry; Cytostatic Agents - metabolism; Cytostatic Agents - pharmacology; Doxorubicin - analogs & derivatives; Doxorubicin - metabolism; Doxorubicin - pharmacology; Drug Design; Drug Resistance, Neoplasm; Ethacrynic Acid - analogs & derivatives; Ethacrynic Acid - chemistry; Ethacrynic Acid - metabolism; Ethacrynic Acid - pharmacology; Female; Glutathione S-Transferase pi - genetics; Glutathione S-Transferase pi - metabolism; Glutathione Transferase - genetics; Glutathione Transferase - metabolism; Humans; Medicin och hälsovetenskap; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Organoplatinum Compounds - chemistry; Organoplatinum Compounds - metabolism; Organoplatinum Compounds - pharmacology; Prodrugs - chemistry; Prodrugs - metabolism; Prodrugs - pharmacology; Rats; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Substrate Specificity; glutathione transferase; drug resistance; cytostatic drug
• ISSN: 1543-8384; 1543-8392; 1543-8392
• DOI: 10.1021/mp2000692

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.