Abstract
Purpose: Sensitizing cancer cells to irradiation is a major challenge in clinical oncology. We aimed to define the signal transduction pathways involved in poly(ADP-ribose) polymerase (PARP) inhibitor-induced radiosensitization in various mammalian cancer lines.
Materials and methods: Clonogenic survival assays and Western blot examinations were performed following telecobalt irradiation of cancer cells in the presence or absence of various combinations of PARP- and selective mitogen-activated protein kinase (MAPK) inhibitors.
Results: HO3089 resulted in significant cytotoxicity when combined with irradiation. In human U251 glioblastoma and A549 lung cancer cell lines, Erk1/2 and JNK/SAPK were found to mediate this effect of HO3089 since inhibitors of these kinases ameliorated it. In murine 4T1 breast cancer cell line, p38 MAPK rather than Erk1/2 or JNK/SAPK was identified as the main mediator of HO3089's radiosensitizing effect. Besides the aforementioned changes in kinase signaling, we detected increased p53, unchanged Bax and decreased Bcl-2 expression in the A549 cell line.
Conclusions: HO3089 sensitizes cancer cells to photon irradiation via proapoptotic processes where p53 plays a crucial role. Activation of MAPK pathways is regarded the consequence of irradiation-induced DNA damage, thus their inhibition can counteract the radiosenzitizing effect of the PARP inhibitor.
Acknowledgements
The authors would like to express their deepest appreciation to Professor Ferenc Gallyas (Department of Biochemistry and Medical Chemistry, Medical School, University of Pecs) and Gyorgy Cserna for their professional and linguistic comments and advice which contributed to the improvement of this manuscript.
Declaration of interest:
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
This work was supported by the Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences, Research Grants from AOK-KA-10-04-2011, AOK-KA-34039-1004/2010, AOK-KA-34039/KA-OTKA/11-04, AOK-KA-34039/10-24, 34039/ KA-OTKA/2011/11-17, OTKA-K-73738, SROP-4.2.2/B-10/ 1-2010-0029 (Supporting Scientific Training of Talented Youth at the University of Pécs), SROP-4.2.1.B-10/2/KONV-2010-0002, Developing the South-Transdanubian Regional University Competitiveness and the Nuclear-Mitochondrial Interactions Research Group, Hungarian Academy of Sciences, PO Box 1000, H-1245 Budapest, Hungary.