title: Characterization of new potential anticancer drugs designed to overcome glutathione transferase mediated resistance.
abstract: 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.
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, SE-17177 Stockholm, Sweden.
authors.forename: Katarina
authors.initials: K
authors.lastname: Johansson
authors.forename: Mika
authors.initials: M
authors.lastname: Ito
authors.forename: Carolien M S
authors.initials: CM
authors.lastname: Schophuizen
authors.forename: Sherin
authors.initials: S
authors.lastname: Mathew Thengumtharayil
authors.forename: Vanina D
authors.initials: VD
authors.lastname: Heuser
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.forename: Miyuki
authors.initials: M
authors.lastname: Shimoji
authors.forename: Marie
authors.initials: M
authors.lastname: Vahter
authors.forename: Wee Han
authors.initials: WH
authors.lastname: Ang
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Dyson
authors.forename: Aya
authors.initials: A
authors.lastname: Shibata
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shuto
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ito
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Abe
authors.forename: Ralf
authors.initials: R
authors.lastname: Morgenstern
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D054697:Cytostatic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D004976:Ethacrynic Acid / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D051549:Glutathione S-Transferase pi / Q000235:genetics / Q000378:metabolism*; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D000970:Antineoplastic Agents; D054697:Cytostatic Agents; D009363:Neoplasm Proteins; D009944:Organoplatinum Compounds; D011355:Prodrugs; D011994:Recombinant Proteins; C570220:ethacraplatin; D004317:Doxorubicin; C122107:microsomal glutathione S-transferase-I; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D004976:Ethacrynic Acid; D002945:Cisplatin