Carcinogenesis Advance Access originally published online on August 18, 2006
Carcinogenesis 2007 28(2):465-470; doi:10.1093/carcin/bgl148
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Microsomal glutathione transferase 1 in anticancer drug resistance
Institute of Environmental Medicine, Division of Biochemical Toxicology, Karolinska Institutet SE-171 77 Stockholm, Sweden
1 Istituto Scientifico San Raffaele, via Olgettina 58 20132 Milano, Italy
2 Lung and Allergy Research, Division of Physiology, National Institute of Environmental Medicine, Karolinska Institutet Stockholm, Sweden
3 Department of Laboratory Medicine, Faculty of Medicine, Chulalongkorn University BKK 10330, Thailand
*To whom correspondence should be addressed. Tel: +46 8 5248 7566; Fax: +46 8 343849; Email: katarina.johansson{at}ki.se
Glutathione transferases (GSTs) are often upregulated in tumors and have been suggested to play an important role in multiple drug resistance in cancer chemotherapy. As a consequence GST-dependent pro-drugs and inhibitors are being developed. Little is known, however, on the potential role of membrane-bound GSTs in drug resistance despite the fact that detoxication of cytostatic drugs and upregulation in tumors has been demonstrated. Therefore, we have studied the involvement of membrane-bound microsomal GST1 (MGST1) in cellular resistance to anticancer drugs. As a tool we have developed a cell system utilizing MCF7 cells stably overexpressing MGST1. Here, we show for the first time that MGST1 can protect cells from several cytostatic drugs, chlorambucil, melphalan and cisplatin in an acute toxicity test (MTT assay) as well as a long-term colony forming efficiency cytotoxicity test. It is of note that these cells do not overexpress multidrug transporters, a prerequisite for protection with certain other GSTs investigated in this system. The cytostatic drugs used comprise both those that are known/predicted to be substrates as well as non-substrates. Thus, the mechanism most probably entails both direct detoxication and downstream protection of the cells from oxidative stress.
Abbreviations: BSA, bovine serum albumin; CDNB, 1-chloro-2,4-dinitrobenzene; CFE, colony forming efficiency; DTNB, 5,5'-dithiobis-(2-nitrobenzoic acid); FBS, fetal bovine serum; G418, geneticin; GSH, glutathione; GST, glutathione transferase; GPX, glutathione peroxidase; MGST1, microsomal glutathione transferase 1; MTT, 3-[4,5-dimethylthiazol-2yl]-2,5-diphenyltetrazolium bromide; NEM, N-ethylmaleimide; SOD, superoxide dismutase
Received May 31, 2006; revised August 9, 2006; accepted August 11, 2006.