Glyoxalase 1 inhibitor therapeutics for multidrug resistant tumors


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

A diagram of a structure

Description automatically generated

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

Thornalley, P.J., Wyatt, C., Davies, N., Edwards, L.G., Kang, Y., Ladan, M.J. and Double, J. (1996) Antitumour activity of S-p-bromobenzylglutathione cyclopentyl diester in vitro and in vivo. Inhibition of glyoxalase I and induction of apoptosis. Biochem. Pharmacol. 51, 1365-1372.

Alhujaily, M., Abbas, H., Xue, M., de la Fuente, A., Rabbani, N. and Thornalley, P.J.  (2021) Studies of glyoxalase 1-linked multidrug resistance reveal glycolysis-derived reactive metabolite, methylglyoxal, is a common contributor in cancer chemotherapy targeting the spliceosome. Frontiers in Oncol 11, 748698

Rabbani, N. and Thornalley, P.J. (2022) Emerging glycation-based therapeutics – glyoxalase 1 inducers and glyoxalase 1 inhibitors. Internat J. Molec. Sci. 23, 2453.