title: Radiosensitization by PARP Inhibition in DNA Repair Proficient and Deficient Tumor Cells: Proliferative Recovery in Senescent Cells.
abstract: Radiotherapy continues to be a primary modality in the treatment of cancer. In addition to promoting apoptosis, radiation-induced DNA damage can promote autophagy and senescence, both of which can theoretically function to prolong tumor survival. In this work, we tested the hypothesis that autophagy and/or senescence could be permissive for DNA repair, thereby facilitating tumor cell recovery from radiation-induced growth arrest and/or cell death. In addition, studies were designed to elucidate the involvement of autophagy and senescence in radiosensitization by PARP inhibitors and the re-emergence of a proliferating tumor cell population. In the context of this work, the relationship between radiation-induced autophagy and senescence was also determined. Studies were performed using DNA repair-proficient HCT116 colon carcinoma cells and a repair-deficient ligase IV(-/-) isogenic cell line. Exposure to radiation promoted a parallel induction of autophagy and senescence that was strongly correlated with the extent of persistent H2AX phosphorylation in both cell lines, however, inhibition of autophagy failed to suppress senescence, indicating that the two responses were dissociable. Exposure to radiation resulted in a transient arrest in the HCT116 cells while arrest was prolonged in the ligase IV(-/-) cells, however, both cell lines ultimately recovered proliferative function, which may reflect maintenance of DNA repair capacity. The PARP inhibitors, olaparib and niraparib, increased the extent of persistent DNA damage induced by radiation exposure as well as the extent of both autophagy and senescence. Neither cell line underwent significant apoptosis by radiation exposure alone or in the presence of the PARP inhibitors. Inhibition of autophagy failed to attenuate radiosensitization, indicating that autophagy was not involved in the action of the PARP inhibitors. As with radiation alone, despite sensitization by PARP inhibition, proliferative recovery was evident within a period of 10-20 days. While inhibition of DNA repair via PARP inhibition may initially sensitize tumor cells to radiation via the promotion of senescence, this strategy does not appear to interfere with proliferative recovery, which could ultimately contribute to disease recurrence.
authors.affiliation: a   Department of Pharmacology and Toxicology, School of Medicine and.|c   Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, 11451, Kingdom of Saudi Arabia; and.
authors.forename: Moureq
authors.initials: M
authors.lastname: Alotaibi
authors.affiliation: a   Department of Pharmacology and Toxicology, School of Medicine and.
authors.forename: Khushboo
authors.initials: K
authors.lastname: Sharma
authors.affiliation: a   Department of Pharmacology and Toxicology, School of Medicine and.
authors.forename: Tareq
authors.initials: T
authors.lastname: Saleh
authors.affiliation: a   Department of Pharmacology and Toxicology, School of Medicine and.
authors.forename: Lawrence F
authors.initials: LF
authors.lastname: Povirk
authors.affiliation: d   Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota 55455.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Hendrickson
authors.affiliation: a   Department of Pharmacology and Toxicology, School of Medicine and.|b   Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, 23298;
authors.forename: David A
authors.initials: DA
authors.lastname: Gewirtz
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001343:Autophagy / Q000187:drug effects / Q000528:radiation effects; D002277:Carcinoma / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy*; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D016922:Cellular Senescence / Q000187:drug effects / Q000528:radiation effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy*; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects / Q000528:radiation effects; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000235:genetics; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage*; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011838:Radiation-Sensitizing Agents; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D011088:DNA Ligases; D000072481:DNA Ligase ATP