title: Effects of the novel DNA dependent protein kinase inhibitor, IC486241, on the DNA damage response to doxorubicin and cisplatin in breast cancer cells.
abstract: The purpose of this study was to determine the degree to which the novel DNA-PKcs inhibitor, IC486241 (ICC), synergizes the cytotoxicity of DNA damaging agents in 3 genetically diverse breast cancer cell lines. The sulforhodamine B (SRB) assay was employed as a primary screening method to determine the in-vitro cytotoxicity and the degree of synergy of ICC in combination with the topoisomerase II inhibitor, doxorubicin, or the DNA cross linking agent, cisplatin. Molecular mechanisms underlying drug toxicity were probed using immunostaining and flow cytometry, as well as, the alkaline comet assay to detect DNA damage. In this study, improved cytotoxicity and significant synergy were observed with both anticancer agents in the presence of nontoxic concentrations of ICC. Moreover, ICC decreased doxorubicin-induced DNA-PKcs autophosphorylation on Ser2056 and increased doxorubicin-induced DNA fragmentation. In conclusion, the novel DNA-PKcs inhibitor, ICC, synergistically sensitized 3 breast cancer cell lines to doxorubicin and cisplatin. Enhanced efficacy of doxorubicin was achieved by inhibiting non-homologous end joining resulting in increased accumulation of DNA damage.
authors.affiliation: Montreal Centre for Experimental Therapeutics in Cancer-Segal Cancer Center-Lady Davis Institute-Jewish General Hospital, McGill University, 3755, Côte Sainte Catherine Road, Montréal, Québec H3T 1E2, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Davidson
authors.forename: Jeremy
authors.initials: J
authors.lastname: Grenier
authors.forename: Veronica
authors.initials: V
authors.lastname: Martinez-Marignac
authors.forename: Lilian
authors.initials: L
authors.lastname: Amrein
authors.forename: May
authors.initials: M
authors.lastname: Shawi
authors.forename: Marc
authors.initials: M
authors.lastname: Tokars
authors.forename: Raquel
authors.initials: R
authors.lastname: Aloyz
authors.forename: Lawrence
authors.initials: L
authors.lastname: Panasci
mesh_terms: D054831:Acridones / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology* / Q000627:therapeutic use; D020552:Comet Assay; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000378:metabolism*; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology* / Q000627:therapeutic use; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D020128:Inhibitory Concentration 50; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D054831:Acridones; D004273:DNA, Neoplasm; C575866:IC486241; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D004317:Doxorubicin; D002945:Cisplatin; D004121:Dimethyl Sulfoxide