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Emerging Glycation-Based Therapeutics-Glyoxalase 1 Inducers and Glyoxalase 1 Inhibitors.
Rabbani, Naila; Thornalley, Paul J.
  • Rabbani N; Department of Basic Medical Science, College of Medicine, Qatar University Health, Qatar University, Doha P.O. Box 2713, Qatar.
  • Thornalley PJ; Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha P.O. Box 34110, Qatar.
Int J Mol Sci ; 23(5)2022 Feb 23.
Article in English | MEDLINE | ID: covidwho-1715405
ABSTRACT
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Diabetes Mellitus, Type 2 / Resveratrol / Glutathione / Hesperidin / Lactoylglutathione Lyase / Neoplasms, Experimental Type of study: Experimental Studies / Observational study / Prognostic study / Randomized controlled trials Limits: Animals / Humans Language: English Year: 2022 Document Type: Article Affiliation country: Ijms23052453

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Diabetes Mellitus, Type 2 / Resveratrol / Glutathione / Hesperidin / Lactoylglutathione Lyase / Neoplasms, Experimental Type of study: Experimental Studies / Observational study / Prognostic study / Randomized controlled trials Limits: Animals / Humans Language: English Year: 2022 Document Type: Article Affiliation country: Ijms23052453