Summary
Glycation of DNA and the spliceosome by methylglyoxal (MG) often contribute to the antiproliferative and apoptotic response of cancer chemotherapy. Glyoxalase 1 (Glo1) of the glyoxalase system has a major role in the metabolism of MG. High expression of Glo1 contributes to multidrug resistance by shielding the spliceosome from MG modification and decreasing survival in the chemotherapy – particularly in the treatment of breast cancer. High Glo1 expression is a negative survival factor in chemotherapy of breast cancer where adjunct therapy with a Glo1 inhibitor may improve treatment outcomes. Cell permeable Glo1 inhibitor prodrugs have been developed to induce severe dicarbonyl stress as a prospective treatment for cancer – particularly for high Glo1 expressing-related multidrug resistant tumors. The prototype Glo1 inhibitor is prodrug S-p-bromobenzylglutathione cyclopentyl diester (BBGD). It has antitumor activity in vitro and in tumor-bearing mice in vivo. In the National Cancer Institute human tumor cell line screen, BBGD was most active against the glioblastoma SNB-19 cell line. Recently, potent antitumor activity was found in glioblastoma multiforme tumor-bearing mice. BBGD has not yet been evaluated clinically. Adjunct chemotherapy with Glo1 inhibitor may improve treatment outcomes in cancer chemotherapy, particularly in breast cancer and glioblastoma multiforme.
Summary scheme
Delivery of glyoxalase 1 inhibitor, S-p-bromobenzylglutathione, into cells by diester modification. Abbreviations: BBG, S-p-bromobenzylglutathione; BBGD, S-p-bromobenzylglutathione cyclopentyl diester; and γ-GT, γ-glutamyl transferase.
Principal publications