title: Inhibition of c-Abl kinase activity renders cancer cells highly sensitive to mitoxantrone.
abstract: Although c-Abl has increasingly emerged as a key player in the DNA damage response, its role in this context is far from clear. We studied the effect of inhibition of c-Abl kinase activity by imatinib with chemotherapy drugs and found a striking difference in cell survival after combined mitoxantrone (MX) and imatinib treatment compared to a panel of other chemotherapy drugs. The combinatory treatment induced apoptosis in HeLa cells and other cancer cell lines but not in primary fibroblasts. The difference in MX and doxorubicin was related to significant augmentation of DNA damage. Transcriptionally active p53 accumulated in cells in which human papillomavirus E6 normally degrades p53. The combination treatment resulted in caspase activation and apoptosis, but this effect did not depend on either p53 or p73 activity. Despite increased p53 activity, the cells arrested in G2 phase became defective in this checkpoint, allowing cell cycle progression. The effect after MX treatment depended partially on c-Abl: Short interfering RNA knockdown of c-Abl rendered HeLa cells less sensitive to MX. The effect of imatinib was decreased by c-Abl siRNA suggesting a role for catalytically inactive c-Abl in the death cascade. These findings indicate that MX has a unique cytotoxic effect when the kinase activity of c-Abl is inhibited. The treatment results in increased DNA damage and c-Abl-dependent apoptosis, which may offer new possibilities for potentiation of cancer chemotherapy.
authors.affiliation: Department of Obstetrics and Gynecology and Joint Clinical Biochemistry Laboratory of Turku University Hospital, Medicity Research Laboratory, University of Turku, Turku, Finland.
authors.forename: Kemal
authors.initials: K
authors.lastname: Alpay
authors.affiliation: Department of Dermatology and MediCity Research Laboratory, University of Turku and Turku University Hospital, Turku, Finland.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Farshchian
authors.affiliation: Department of Cell Biology and Anatomy, University of Turku, Turku, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Tuomela
authors.affiliation: Cell Imaging Core, Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
authors.forename: Jouko
authors.initials: J
authors.lastname: Sandholm
authors.affiliation: Department of Obstetrics and Gynecology and Joint Clinical Biochemistry Laboratory of Turku University Hospital, Medicity Research Laboratory, University of Turku, Turku, Finland.
authors.forename: Kaappo
authors.initials: K
authors.lastname: Aittokallio
authors.affiliation: Department of Dermatology and MediCity Research Laboratory, University of Turku and Turku University Hospital, Turku, Finland.
authors.forename: Elina
authors.initials: E
authors.lastname: Siljamäki
authors.affiliation: VTT Health, VTT Technical Research Centre of Finland, Turku, Finland.
authors.forename: Marko
authors.initials: M
authors.lastname: Kallio
authors.affiliation: Department of Dermatology and MediCity Research Laboratory, University of Turku and Turku University Hospital, Turku, Finland.
authors.forename: Veli-Matti
authors.initials: VM
authors.lastname: Kähäri
authors.affiliation: Department of Obstetrics and Gynecology and Joint Clinical Biochemistry Laboratory of Turku University Hospital, Medicity Research Laboratory, University of Turku, Turku, Finland.
authors.forename: Sakari
authors.initials: S
authors.lastname: Hietanen
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000068877:Imatinib Mesylate; D008942:Mitoxantrone / Q000494:pharmacology*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D009856:Oncogene Proteins, Viral / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D009856:Oncogene Proteins, Viral; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D059005:Topoisomerase II Inhibitors; D016159:Tumor Suppressor Protein p53; D000068877:Imatinib Mesylate; D008942:Mitoxantrone; D016315:Proto-Oncogene Proteins c-abl; D053148:Caspase 3; D053179:Caspase 7