Protecting the genome: defence against nucleotide glycation and emerging role of glyoxalase I overexpression in multidrug resistance in cancer chemotherapy
Protecting the genome: defence against nucleotide glycation and emerging role of glyoxalase I overexpression in multidrug resistance in cancer chemotherapy
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DOI：
10.1042/bst0311372
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发表时间：
2003-12-01
影响因子：
3.9
通讯作者：
Thornalley, PJ
中科院分区：
文献类型：
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作者：
Thornalley, PJ
DNA 中核苷酸的糖化形成 AGE（高级糖化终产物）。核苷酸AGEs是：源自乙二醛的咪唑嘌呤酮衍生物dG-G {3-(2'-脱氧核糖基)-6,7-二氢-6,7-二羟基咪唑[2,3-b]嘌呤-9(8)酮}、CMdG（N-2-羧甲基脱氧鸟苷）和gdC（5-羟乙酰脱氧胞苷），dG-MG源自甲基乙二醛的{6,7-二氢-6,7-二羟基-6-甲基咪唑-[2,3-b]嘌呤-9(8)酮}、dG-MG(2)[N-2,7-双-(1-羟基-2-氧代丙基)脱氧鸟苷]和CEdG[N-2-(1-羧乙基)脱氧鸟苷]和dG-3DG [N-2-(1-氧代-2,4,5,6-四羟基己基)脱氧鸟苷]衍生自3-脱氧葡萄糖醛酮等。乙二醛和甲基乙二醛诱导多碱基缺失和碱基对取代 - 主要发生在 G:C 位点，具有 G:C --> C:G 和 G:C --> T:A 颠换。乙二醛酶 I、醛还原酶和脱氢酶对核苷酸糖基化的抑制以及碱基切除修复可保护和恢复 DNA 免受糖基化损伤。 DNA 糖化的影响在糖尿病和尿毒症中最为明显。 DNA 糖化引起的突变可以解释非膳食碳水化合物摄入量与结直肠癌发病率之间的联系。在耐药肿瘤细胞中发现了乙二醛酶 I 的过度表达，这可能是针对 DNA 糖化的酶保护作用产生不良影响的一个例子。乙二醛酶 I 的实验性过度表达赋予了对药物诱导的细胞凋亡的抵抗力。在人类白血病和肺癌细胞中发现了乙二醛酶 I 介导的耐药性。甲基乙二醛介导的 DNA 糖化可能会导致某些抗肿瘤药物的细胞毒性，这是由于聚（ADP-核糖）聚合酶消耗 NAD+、磷酸三糖浓度显着增加以及甲基乙二醛形成增加的结果。 S-p-Bromobenzylglutathione cyclopentyl diester 是一种细胞渗透性乙二醛酶 I 抑制剂。它可以对抗耐药性，是对抗肺癌和前列腺癌的有效抗肿瘤剂。在浸润性卵巢癌和乳腺癌中也发现了乙二醛酶 I 过度表达。
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-carboxymethyideoxyguanosine) 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.