title: Hypersensitivity of tumor cell lines with microsatellite instability to DNA double strand break producing chemotherapeutic agent bleomycin.
abstract: Genetic or epigenetic inactivation of DNA mismatch repair genes results in a strong mutator phenotype, known as the microsatellite mutator phenotype or microsatellite instability (MSI). This mutator phenotype causes mutations in genes responsible for the regulation of cell growth and survival/death and thus promotes the development and progression of tumors. In addition to such tumorigenic lesions, mutations in genes of other types of DNA repair, for example, DNA double-strand break (DNA DSB) repair, are found in tumor cells with MSI. We report here that the majority of MSI-positive tumor cell lines of different tissue origins (endometrial, ovarian, prostate, and colorectal carcinomas) are hypersensitive to bleomycin, a DNA DSB producing chemotherapeutic drug. We suggest that this hypersensitivity may be a result of inactivation of the DNA DSB repair activity by concomitant mutations of different DNA DSB repair genes. To provide experimental support to this hypothesis, we show that the subclones of the MSI-positive colorectal cancer cell line HCT-8 that bear heterozygous frameshift mutations in the DNA DSB repair gene DNA-PK(CS) are more sensitive to a combined treatment with bleomycin and the DNA protein kinase inhibitor LY294002 than the original HCT-8 cells, which are wild type for this gene. These results may be useful in designing therapies for MSI-positive cancer.
authors.affiliation: The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Hai-Ri
authors.initials: HR
authors.lastname: Li
authors.forename: Elena I
authors.initials: EI
authors.lastname: Shagisultanova
authors.forename: Kentaro
authors.initials: K
authors.lastname: Yamashita
authors.forename: Zhe
authors.initials: Z
authors.lastname: Piao
authors.forename: Manuel
authors.initials: M
authors.lastname: Perucho
authors.forename: Sergei R
authors.initials: SR
authors.lastname: Malkhosyan
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001761:Bleomycin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics*; D004273:DNA, Neoplasm / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D016368:Frameshift Mutation; D016158:Genes, p53 / Q000235:genetics; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases / Q000235:genetics
chemical_list: D000903:Antibiotics, Antineoplastic; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D001761:Bleomycin; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D017346:Protein Serine-Threonine Kinases