The Putative Glyoxalase 1 Inhibitor Piceatannol Exhibits Both Anxiolytic-like and Antitumor Effects in Mice.

BACKGROUND/AIM: This study aimed to determine the anxiolytic effect of a putative glyoxalase 1 inhibitor, piceatannol, as well as its antitumor activities on the stress-induced tumor growth of Lewis lung carcinoma. MATERIALS AND METHODS: The anxiolytic activities of piceatannol (1-30 mg/kg) were assessed using the elevated plus maze (EPM) test. We also evaluated the pharmacological modulation of stress-induced tumor growth; the mice were treated with piceatannol (3 and 30 mg/kg) from the 10th day till the 19th day after administration of the LLC cells. RESULTS: At the low dose (3 mg/kg), piceatannol significantly increased the time spent in the open arms of the EPM test when compared with the vehicle. At higher doses (30 mg/kg), it significantly suppressed the stress-induced enhancement of tumor growth. CONCLUSION: A low dose of piceatannol exerts an anxiolytic effect, and high doses have an antitumor effect.

Methylglyoxal-induced dicarbonyl stress in aging and disease: first steps towards glyoxalase 1-based treatments.

Dicarbonyl stress is the abnormal accumulation of dicarbonyl metabolites leading to increased protein and DNA modification contributing to cell and tissue dysfunction in aging and disease. It is produced by increased formation and/or decreased metabolism of dicarbonyl metabolites. MG (methylglyoxal) is a dicarbonyl metabolite of relatively high flux of formation and precursor of the most quantitatively and functionally important spontaneous modifications of protein and DNA clinically. Major MG-derived adducts are arginine-derived hydroimidazolones of protein and deoxyguanosine-derived imidazopurinones of DNA. These are formed non-oxidatively. The glyoxalase system provides an efficient and essential basal and stress-response-inducible enzymatic defence against dicarbonyl stress by the reduced glutathione-dependent metabolism of methylglyoxal by glyoxalase 1. The GLO1 gene encoding glyoxalase 1 has low prevalence duplication and high prevalence amplification in some tumours. Dicarbonyl stress contributes to aging, disease and activity of cytotoxic chemotherapeutic agents. It is found at a low, moderate and severe level in obesity, diabetes and renal failure respectively, where it contributes to the development of metabolic and vascular complications. Increased glyoxalase 1 expression confers multidrug resistance to cancer chemotherapy and has relatively high prevalence in liver, lung and breast cancers. Studies of dicarbonyl stress are providing improved understanding of aging and disease and the basis for rational design of novel pharmaceuticals: glyoxalase 1 inducers for obesity, diabetes and cardiovascular disease and glyoxalase 1 inhibitors for multidrug-resistant tumours. The first clinical trial of a glyoxalase 1 inducer in overweight and obese subjects showed improved glycaemic control, insulin resistance and vascular function.