Effect of gliclazide on nucleotide excision repair (NER) and non-homologous DNA end joining (NHEJ) in normal and cancer cells.
The results of clinical studies revealed that gliclazide may reduce the risk of cancer in type 2 diabetic patients (T2DM), although the mechanism of possible protective effect is not sufficiently explored. The increased level of DNA damage and impaired DNA repair system in diabetes mellitus may play a substantial role in neoplastic transformation. Recently, we have demonstrated that gliclazide protected DNA against damage introduced by the oxidative stress, but its action on the DNA repair mechanisms is unclear. Therefore, the aim of this study was to assess whether gliclazide has any effect on the DNA repair pathways, e.g. nucleotide excision repair (NER) and non-homologous end joining (NHEJ). NER activity was assessed in the extract of human lymphocytes and pancreatic cancer cells (PANC-1) treated or not with gliclazide by use of an UV-irradiated plasmid as a substrate and by quantitative PCR performed to evaluate the efficacy of the removal of UV-induced lesions from the p53 gene by intact cells. The efficacy of NHEJ pathway was examined by a simple and rapid in vitro assay based on fluorescent detection of repair products. We did not observe significant differences between the efficiency of NER and NHEJ for extracts of lymphocytes alone and lymphocytes treated with gliclazide. Contrary, gliclazide increased the efficacy of NER (46.0% vs. 84.0%, p<0.01) and NHEJ (58.0% vs. 66.0%, p<0.05) in PANC-1 cells. In conclusion, the present study showed that gliclazide did not affect NER and NHEJ in human normal cells, but it may stimulate DNA repair in cancer cells.
Sliwinska
A
A
Department of Internal Medicine, Diabetology and Clinical Pharmacology, Medical University of Lodz, Lodz, Poland.
Sliwinski
T
T
Kasznicki
J
J
Drzewoski
J
J
D000293:Adolescent; D000328:Adult; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics*; D045744:Cell Line, Tumor; D004247:DNA / Q000096:biosynthesis / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D004260:DNA Repair / Q000187:drug effects*; D016158:Genes, p53; D005907:Gliclazide / Q000494:pharmacology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008214:Lymphocytes / Q000187:drug effects*; D008297:Male; D014466:Ultraviolet Rays; D055815:Young Adult
D007004:Hypoglycemic Agents; D004247:DNA; D005907:Gliclazide