title: Haloenol lactone: a new synergist of chemotherapy in vitro.
abstract: Over-expression of glutathione S-transferases (GST) has been found to play a significant role in multiple drug resistance in cancer chemotherapy. To combat GST-mediated drug resistance, GST inhibitors are being studied as potential synergists for effective cancer chemotherapy. We have designed and synthesized a haloenol lactone derivative as a mechanism-based inactivator of GST-pi isozyme. In the current study, we examined the inhibitory effect of the haloenol lactone compound on GST of a human renal carcinoma cell line UOK130 and found that this compound shows time-dependent GST inhibition in these cancer cells. The enzyme activity lost upon incubation with the haloenol lactone could not be restored by extensive dialysis against buffer. Pretreatment of the cancer cells with 1.0 microM of haloenol lactone increased cytotoxicity induced by cisplatin in the UOK130 cell line. This report further supports the possibility of synergizing alkylating agents in cancer chemotherapy by use of selective GST inhibitors.
authors.affiliation: Department of Environmental Toxicology, University of California at Davis, Davis, California 95616, USA.
authors.forename: J
authors.initials: J
authors.lastname: Zheng
authors.forename: G T
authors.initials: GT
authors.lastname: Wurz
authors.forename: T B
authors.initials: TB
authors.lastname: Cadman
authors.forename: M W
authors.initials: MW
authors.lastname: Degregorio
authors.forename: A D
authors.initials: AD
authors.lastname: Jones
authors.forename: B D
authors.initials: BD
authors.lastname: Hammock
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000633:toxicity; D000970:Antineoplastic Agents / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000633:toxicity*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000633:toxicity; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007680:Kidney Neoplasms; D007700:Kinetics; D014407:Tumor Cells, Cultured
chemical_list: C101132:3-cinnamyl-5-bromomethylidenetetrahydro-2-furanone; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D005982:Glutathione Transferase; D015107:4-Butyrolactone; D002945:Cisplatin