Abstract
Emergence of resistance to anticancer agents is a serious problem in cancer chemotherapy. We studied on the suppression of anticancer drug resistance targetting the overexpressed glutathione (GSH) in apoptosis-resistant tumor cells and glyoxalase I (GloI). GloI is an enzyme that plays a role in the detoxification of methylglyoxal utilizing GSH as an essential cofactor. Inhibitors of GloI have been found to exhibit antiproliferative effects on cancerous cells. Hence, potent GloI inhibitors could proved to be valuable anticancer agents. COTC, an inhibitor of GloI isolated from the culture broth of Streptomyces griseosporeus, had no effect on GloI in the absence of GSH. We reexamined the reaction of COTC with GSH and found that STCG was the real inhibitor of GloI. AsPC-1 cells show the drug-resistance against anticancer drugs because of the over-expression of GSH. When AsPC-1 cells were treated with several anticancer drugs in the presence of COTC, the sensitivity of AsPC-1 cells to CDDP and melphalan was significantly increased. Next, we synthesized ACDC containing adriamycin as an anticancer drug in a molecule. Treatment of ACDC with GSH released adriamycin and SDCG. Evaluation of ACDC against adriamycin-resistant L1210 cells showed significant increase of sensitivity and the prolonged life span of mice bearing P388 leukemia was observed.
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