title: Synergistic cytotoxicity of busulfan, melphalan, gemcitabine, panobinostat, and bortezomib in lymphoma cells.
abstract: DNA alkylators busulfan (B) and melphalan (M) act synergistically with gemcitabine (G) against lymphoma cells. To further improve the cytotoxicity, we combined them with the histone deacetylase inhibitor panobinostat (P) and proteasome inhibitor bortezomib (V). Lymphoma cell lines U937 and J45.01, and patient-derived cell samples were exposed to these drugs and the effects on cell proliferation and apoptosis were quantified. The combination BMGPV was found to exert strong synergistic cytotoxicity. Drug exposure to these cells activated the ATM pathway and modified histones at the epigenetic level. Cell death was triggered by the production of reactive oxygen species (ROS), permeabilization of the mitochondrial membrane, upregulation of proapoptotic factors, and activation of caspases. Downregulation of anti-apoptotic proteins c-MYC, MCL-1, and BCL-2 and inhibition of the prosurvival PI3K-AKT-mTOR pathway, culminated in apoptosis. The results of this study support a clinical trial using BMGPV as a possible pre-transplant conditioning regimen for relapsed/refractory lymphoma patients.
authors.affiliation: a Department of Hematology , Singapore General Hospital , Singapore ;|b Department of Stem Cell Transplantation and Cellular Therapy , UT MD Anderson Cancer Center , Houston , TX , USA ;
authors.forename: Esmeralda C
authors.initials: EC
authors.lastname: Teo
authors.affiliation: b Department of Stem Cell Transplantation and Cellular Therapy , UT MD Anderson Cancer Center , Houston , TX , USA ;
authors.forename: Benigno C
authors.initials: BC
authors.lastname: Valdez
authors.affiliation: b Department of Stem Cell Transplantation and Cellular Therapy , UT MD Anderson Cancer Center , Houston , TX , USA ;|c Department of Hematology , West China Hospital, Sichuan University , Sichuan , China.
authors.forename: Jie
authors.initials: J
authors.lastname: Ji
authors.affiliation: b Department of Stem Cell Transplantation and Cellular Therapy , UT MD Anderson Cancer Center , Houston , TX , USA ;
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: b Department of Stem Cell Transplantation and Cellular Therapy , UT MD Anderson Cancer Center , Houston , TX , USA ;
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: b Department of Stem Cell Transplantation and Cellular Therapy , UT MD Anderson Cancer Center , Houston , TX , USA ;
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Brammer
authors.affiliation: b Department of Stem Cell Transplantation and Cellular Therapy , UT MD Anderson Cancer Center , Houston , TX , USA ;
authors.forename: Chitra
authors.initials: C
authors.lastname: Hosing
authors.affiliation: b Department of Stem Cell Transplantation and Cellular Therapy , UT MD Anderson Cancer Center , Houston , TX , USA ;
authors.forename: Yago
authors.initials: Y
authors.lastname: Nieto
authors.affiliation: b Department of Stem Cell Transplantation and Cellular Therapy , UT MD Anderson Cancer Center , Houston , TX , USA ;
authors.forename: Richard E
authors.initials: RE
authors.lastname: Champlin
authors.affiliation: b Department of Stem Cell Transplantation and Cellular Therapy , UT MD Anderson Cancer Center , Houston , TX , USA ;
authors.forename: Borje S
authors.initials: BS
authors.lastname: Andersson
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000069286:Bortezomib / Q000494:pharmacology*; D002066:Busulfan / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D008558:Melphalan / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008875:Middle Aged; D000077767:Panobinostat; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014407:Tumor Cells, Cultured; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D000069286:Bortezomib; D002066:Busulfan; D003841:Deoxycytidine; D006877:Hydroxamic Acids; D007211:Indoles; D008558:Melphalan; D000077767:Panobinostat; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D017382:Reactive Oxygen Species; D058570:TOR Serine-Threonine Kinases; D000093542:Gemcitabine
keywords: Conditioning regimen; lymphoma; stem cell transplant