Assessment of In Vivo and In Vitro Genotoxicity of Glibenclamide in Eukaryotic Cells

Abstract

Glibenclamide is an oral hypoglycemic drug commonly prescribed for the treatment of type 2 diabetes mellitus, whose anti-tumor activity has been recently described in several human cancer cells. The mutagenic potential of such an antidiabetic drug and its recombinogenic activity in eukaryotic cells were evaluated, the latter for the first time. The mutagenic potential of glibenclamide in therapeutically plasma (0.6 μM) and higher concentrations (10 μM, 100 μM, 240 μM and 480 μM) was assessed by the in vitro mammalian cell micronucleus test in human lymphocytes. Since the loss of heterozygosity arising from allelic recombination is an important biologically significant consequence of oxidative damage, the glibenclamide recombinogenic activity at 1 μM, 10 μM and 100 μM concentrations was evaluated by the in vivo homozygotization assay. Glibenclamide failed to alter the frequency of micronuclei between 0.6 μM and 480 μM concentrations and the cytokinesis block proliferation index between 0.6 μM and 240 μM concentrations. On the other hand, glibenclamide changed the cell-proliferation kinetics when used at 480 μM. In the homozygotization assay, the homozygotization indices for the analyzed markers were lower than 2.0 and demonstrated the lack of recombinogenic activity of glibenclamide. Data in the current study demonstrate that glibenclamide, in current experimental conditions, is devoid of significant genotoxic effects. This fact encourages further investigations on the use of this antidiabetic agent as a chemotherapeutic drug.

The Use of Glyburide Compared With Other Sulfonylureas and the Risk of Cancer in Patients With Type 2 Diabetes

“…Biologically, animal models have ruled out direct tumorigenic activity of glyburide and, conversely, supported an antiproliferative effect of all sulfonylureas (26)(27)(28)(29)(30). On the other hand, the current findings are consistent with an ROS-inducing effect that seems to pertain to glyburide (14) and not to other sulfonylureas, which in turn appear to exert a protective activity against ROS (31,32).…”

Increased Micronuclei Frequency in Oral and Lingual Epithelium of Treated Diabetes Mellitus Patients

“…In contrast, there are studies showing that short-term exposure to metformin does not increase micronuclei in human cells [ 41 , 42 ]. There are oral drugs such as glibenclamide that report no increase of micronuclei frequencies in treated DM2 patients [ 43 ]. Similarly, there is not a study demonstrating any direct role of insulin treatment on micronuclei induction on DM1 patients [ 23 , 44 – 47 ].…”

Glibenclamide induces apoptosis by activating reactive oxygen species dependent JNK pathway in hepatocellular carcinoma cells

“…Now increasing evidence reveals that Gli exerts anti-tumor effects in many neoplastic cell lines [ 11 , 12 ]. Its genotoxicity in cancer cells or normal cells have been heatingly discussed in recent years, both in vitro and in vivo [ 13 – 15 ].…”