The abnormal accumulation of
methylglyoxal (MG) leading to increased glycation of
protein and
DNA has emerged as an important metabolic stress, dicarbonyl stress, linked to aging, and disease. Increased MG glycation produces inactivation and misfolding of
proteins, cell dysfunction, activation of the unfolded protein response, and related low-grade
inflammation. Glycation of
DNA and the spliceosome contribute to an antiproliferative and apoptotic response of high, cytotoxic levels of MG. Glyoxalase 1 (Glo1) of the glyoxalase system has a major role in the metabolism of MG. Small molecule inducers of Glo1, Glo1 inducers, have been developed to alleviate dicarbonyl stress as a prospective treatment for the prevention and early-stage reversal of
type 2 diabetes and prevention of vascular complications of diabetes. The first clinical trial with the Glo1 inducer,
trans-resveratrol and
hesperetin combination (tRES-HESP)-a randomized, double-blind, placebo-controlled crossover phase 2A study for correction of
insulin resistance in
overweight and obese subjects, was completed successfully. tRES-HESP corrected
insulin resistance, improved dysglycemia, and low-grade
inflammation. 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. High Glo1 expression is a negative survival factor in
chemotherapy of
breast cancer where adjunct
therapy with a Glo1 inhibitor may improve treatment outcomes. BBGD has not yet been evaluated clinically. Glycation by MG now appears to be a pathogenic process that may be pharmacologically manipulated for therapeutic outcomes of potentially important clinical impact.