title: The PARP inhibitor olaparib enhances the cytotoxicity of combined gemcitabine, busulfan and melphalan in lymphoma cells.
abstract: The combination of gemcitabine (Gem), busulfan (Bu), and melphalan (Mel) is a promising regimen for autologous stem-cell transplantation (SCT) for lymphomas. To further improve the efficacy of [Gem + Bu + Mel], we added poly(ADP-ribose) polymerase (PARP) inhibitor olaparib (Ola). We hypothesized that Ola would inhibit the repair of damaged DNA caused by [Gem + Bu + Mel]. Exposure of J45.01 and Toledo cell lines to IC10-20of individual drug inhibited proliferation by 6-16%; [Gem + Bu + Mel] by 20-27%; and [Gem + Bu + Mel + Ola] by 61-67%. The synergistic cytotoxicity of the four-drug combination may be attributed to activation of the DNA-damage response, inhibition of PARP activity and DNA repair, decreased mitochondrial membrane potential, increased production of reactive oxygen species, and activation of the SAPK/JNK stress signaling pathway, all of which may enhance apoptosis. Similar observations were obtained using mononuclear cells isolated from patients with T-cell lymphocytic leukemia. Our results provide a rationale for undertaking clinical trials of this drug combination for lymphoma patients undergoing SCT.
authors.affiliation: a Department of Stem Cell Transplantation and Cellular Therapy , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.
authors.forename: Benigno C
authors.initials: BC
authors.lastname: Valdez
authors.affiliation: a Department of Stem Cell Transplantation and Cellular Therapy , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: b Department of Experimental Oncology , Cross Cancer Institute , Edmonton , Canada.
authors.forename: David
authors.initials: D
authors.lastname: Murray
authors.affiliation: a Department of Stem Cell Transplantation and Cellular Therapy , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: a Department of Stem Cell Transplantation and Cellular Therapy , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.
authors.forename: Yago
authors.initials: Y
authors.lastname: Nieto
authors.affiliation: a Department of Stem Cell Transplantation and Cellular Therapy , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Champlin
authors.affiliation: a Department of Stem Cell Transplantation and Cellular Therapy , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.
authors.forename: Borje S
authors.initials: BS
authors.lastname: Andersson
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D002066:Busulfan / Q000008:administration & dosage; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004260:DNA Repair; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004357:Drug Synergism; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D008297:Male; D008558:Melphalan / Q000008:administration & dosage; D008875:Middle Aged; D010793:Phthalazines / Q000008:administration & dosage; D010879:Piperazines / Q000008:administration & dosage; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D000093542:Gemcitabine
chemical_list: D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D017382:Reactive Oxygen Species; D003841:Deoxycytidine; D002066:Busulfan; D008558:Melphalan; C531550:olaparib; D000093542:Gemcitabine
keywords: DNA repair; Olaparib; busulfan; gemcitabine; melphalan; stem cell transplantation