Protecting the genome: defence against nucleotide glycation and emerging role of glyoxalase I overexpression in multidrug resistance in cancer chemotherapy

Abstract

Glycation of nucleotides in DNA forms AGEs (advanced glycation end-products). Nucleotide AGEs are: the imidazopurinone derivative dG-G [3-(2'-deoxyribosyl)-6,7-dihydro-6,7-dihydroxyimidazo[2,3-b]purin-9(8)one], CMdG ( N (2)-carboxymethyldeoxyguanosine) and gdC (5-glycolyldeoxycytidine) derived from glyoxal, dG-MG [6,7-dihydro-6,7-dihydroxy-6-methylimidazo-[2,3-b]purine-9(8)one], dG-MG(2) [ N (2),7-bis-(1-hydroxy-2-oxopropyl)deoxyguanosine] and CEdG [ N (2)-(1-carboxyethyl)deoxyguanosine] derived from methylglyoxal, and dG-3DG [ N (2)-(1-oxo-2,4,5,6-tetrahydroxyhexyl)deoxyguanosine] derived from 3-deoxyglucosone and others. Glyoxal and methylglyoxal induce multi-base deletions, and base-pair substitutions - mostly occurring at G:C sites with G:C-->C:G and G:C-->T:A transversions. Suppression of nucleotide glycation by glyoxalase I and aldehyde reductases and dehydrogenases, and base excision repair, protects and recovers DNA from damaging glycation. The effects of DNA glycation may be most marked in diabetes and uraemia. Mutations arising from DNA glycation may explain the link of non-dietary carbohydrate intake to incidence of colorectal cancer. Overexpression of glyoxalase I was found in drug-resistant tumour cells and may be an example of an undesirable effect of the enzymatic protection against DNA glycation. Experimental overexpression of glyoxalase I conferred resistance to drug-induced apoptosis. Glyoxalase I-mediated drug resistance was found in human leukaemia and lung carcinoma cells. Methylglyoxal-mediated glycation of DNA may contribute to the cytotoxicity of some antitumour agents as a consequence of depletion of NAD(+) by poly(ADP-ribose) polymerase, marked increases in triosephosphate concentration and increased formation of methylglyoxal. S - p -Bromobenzylglutathione cyclopentyl diester is a cell-permeable glyoxalase I inhibitor. It countered drug resistance and was a potent antitumour agent against lung and prostate carcinoma. Glyoxalase I overexpression was also found in invasive ovarian cancer and breast cancer.

Glyoxalase I Is Critical for Human Retinal Capillary Pericyte Survival under Hyperglycemic Conditions

“…Induction of apoptosis by MGO through glycation of DNA should also be considered. A number of studies described nucleotide AGEs, including MGO-derived adducts (54), that affect the integrity of the target DNA and increase apoptosis via G 1 growth arrest (55).…”

HMGB1, S100 proteins and other RAGE ligands in cancer - markers, mediators and putative therapeutic targets

“…S100A12, a RAGE ligand may decrease the expression of glyoxalase I and impair the degradation of AGEs 30 . Mutations arising from DNA glycation could explain the link of carbohydrate intake to incidence of colorectal cancer and increased risk of cancer in patients with diabetes 29 . Suppression of nucleotide glycation by glyoxalase I protects DNA not only in normal, but also in cancer cells from damage and contributes to its recovery and experimental overexpression of glyoxalase I confers the cancer cells with resistance to drug-induced apoptosis 31 .…”

“…Methylglyoxal, a precursor of AGEs and potent inducer of apoptosis, may be degraded by the system of glutathione-dependent glyoxalases composed of glyoxalase I (Glo I) and glyoxalase II (Glo II) enzymes. Glyoxal and methylglyoxal bind to DNA and induce multibase deletions and base-pair substitutions, mostly occurring at G:C sites 29 ( Table 1). Glyoxalase may be activated in chronic inflammatory diseases and in diabetes and uremia to counteract the increased carbonyl and oxidative stress with the overproduction of AGEs, ALEs and AOPP (ref.…”

Glyoxalase biochemistry

“…Protein crosslinks have also been identified and include MG-lysine dimer (MOLD) and MG-derived imidazolium crosslinking (MODIC) crosslinks (14,115) (Figure 11). DNA modification by MG can also occur and include adduct formation with deoxyguanosine nucleotides (110,116,117).…”