title: Rationale for poly(ADP-ribose) polymerase (PARP) inhibitors in combination therapy with camptothecins or temozolomide based on PARP trapping versus catalytic inhibition.
abstract: We recently showed that poly(ADP-ribose) polymerase (PARP) inhibitors exert their cytotoxicity primarily by trapping PARP-DNA complexes in addition to their NAD(+)-competitive catalytic inhibitory mechanism. PARP trapping is drug-specific, with olaparib exhibiting a greater ability than veliparib, whereas both compounds are potent catalytic PARP inhibitors. Here, we evaluated the combination of olaparib or veliparib with therapeutically relevant DNA-targeted drugs, including the topoisomerase I inhibitor camptothecin, the alkylating agent temozolomide, the cross-linking agent cisplatin, and the topoisomerase II inhibitor etoposide at the cellular and molecular levels. We determined PARP-DNA trapping and catalytic PARP inhibition in genetically modified chicken lymphoma DT40, human prostate DU145, and glioblastoma SF295 cancer cells. For camptothecin, both PARP inhibitors showed highly synergistic effects due to catalytic PARP inhibition, indicating the value of combining either veliparib or olaparib with topoisomerase I inhibitors. On the other hand, for temozolomide, PARP trapping was critical in addition to catalytic inhibition, consistent with the fact that olaparib was more effective than veliparib in combination with temozolomide. For cisplatin and etoposide, olaparib only showed no or a weak combination effect, which is consistent with the lack of involvement of PARP in the repair of cisplatin- and etoposide-induced lesions. Hence, we conclude that catalytic PARP inhibitors are highly effective in combination with camptothecins, whereas PARP inhibitors capable of PARP trapping are more effective with temozolomide. Our study provides insights in combination treatment rationales for different PARP inhibitors.
authors.affiliation: Developmental Therapeutics Branch, Laboratory of Molecular Pharmacology, Center for Cancer Research (Ju.M., J.H.D., Y.P.), National Clinical Target Validation Laboratory (Y.Z., J.J.), and Division of Cancer Treatment and Diagnosis (Jo.M., J.H.D.), National Cancer Institute, National Institutes of Health, Bethesda, Maryland; and Department of Radiation Genetics, Graduate School of Medicine, Kyoto University, Yoshidakonoe, Sakyo-ku, Kyoto, Japan (Ju.M., S.T.).
authors.forename: Junko
authors.initials: J
authors.lastname: Murai
authors.forename: Yiping
authors.initials: Y
authors.lastname: Zhang
authors.forename: Joel
authors.initials: J
authors.lastname: Morris
authors.forename: Jiuping
authors.initials: J
authors.lastname: Ji
authors.forename: Shunichi
authors.initials: S
authors.lastname: Takeda
authors.forename: James H
authors.initials: JH
authors.lastname: Doroshow
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001562:Benzimidazoles / Q000008:administration & dosage / Q000494:pharmacology; D002166:Camptothecin / Q000008:administration & dosage / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002645:Chickens; D004249:DNA Damage; D004260:DNA Repair; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D010793:Phthalazines / Q000008:administration & dosage / Q000494:pharmacology; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D000077204:Temozolomide
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C521013:veliparib; D003606:Dacarbazine; C531550:olaparib; D002166:Camptothecin; D000077204:Temozolomide