Journal Article

hMSH3 overexpression and cellular response to cytotoxic anticancer agents

Rita Pepponi, Grazia Graziani, Sabrina Falcinelli, Patrizia Vernole, Lauretta Levati, Pedro Miguel Lacal, Elena Pagani, Enzo Bonmassar, Josef Jiricny and Stefania D'Atri

in Carcinogenesis

Volume 22, issue 8, pages 1131-1137
Published in print August 2001 | ISSN: 0143-3334
Published online August 2001 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/22.8.1131
hMSH3 overexpression and cellular response to cytotoxic anticancer agents

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Mutations or transcriptional silencing of mismatch repair genes have been linked with tumour cell resistance to O6-guanine methylating agents, 6-thioguanine, cisplatin, doxorubicin and etoposide. Recently, it has been demonstrated that overexpression of the MSH3 protein is associated with depletion of the mismatch binding factor MutSα, and then with a marked reduction in the efficiency of base/base mismatch repair. In the present study we evaluated sensitivity of the HL-60 cell line and its methotrexate-resistant subline HL-60R, which overexpresses the hMSH3 gene, to a panel of chemotherapeutic agents. Cell growth inhibition induced by temozolomide, 6-thioguanine and N-methyl-N′-nitro-N-nitrosoguanidine was significantly lower in the hMSH3-overexpressing HL-60R cell line as compared with the HL-60 parental line. Moreover, HL-60R cells were more resistant than HL-60 cells to chromosome aberrations induced by either N-methyl-N′-nitro-N-nitrosoguanidine or temozolomide, and to apoptosis triggered by the latter drug. Both cell lines were equally susceptible to growth inhibition induced by cisplatin, etoposide or doxorubicin. In addition, HL-60 and HL-60R cells showed comparable sensitivity to the clastogenic and apoptotic effects of cisplatin and etoposide. These results further confirm that loss of base/base mismatch repair is the most important molecular mechanism involved in cell resistance to O6-guanine methylating agents and 6-thioguanine. However, the status of the mismatch repair system could still influence tumour cell sensitivity to cisplatin, etoposide and doxorubicin, depending on the specific component of the system that is lost, and on the genetic background of the cell.

Keywords: BG, O6-benzylguanine; BSA, bovine serum albumin; CM, complete medium; DHFR, dihydrofolate reductase; IDLs, insertion/ deletion loops; MMR, mismatch repair; MNNG, N-methyl-N′-nitro-N-nitrosoguanidine; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; MTX, methotrexate; O6-G, O6-guanine; OGAT, O6-alkylguanine-DNA alkyltransferase; O6-MeG, O6-methylguanine; PBS, phosphate buffered saline; PI, propidium iodide; 6-TG, 6-thioguanine; TMZ, temozolomide, 8-carbamoyl-3-methyl-imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one.

Journal Article.  6471 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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