title: The mitochondria-independent cytotoxic effect of nelfinavir on leukemia cells can be enhanced by sorafenib-mediated mcl-1 downregulation and mitochondrial membrane destabilization.
abstract: BACKGROUND
  Nelfinavir is an HIV protease inhibitor that has been used for a long period of time to treat HIV-infected individuals. It has recently emerged that nelfinavir could represent a prospective new anti-cancer drug, prompting us to test the effect of nelfinavir on leukemia cells.
  
  
  METHODS
  By combining in vitro and ex vivo studies, the effect of nelfinavir on leukemia cells and non-malignant, bone marrow-derived tissue cells was analyzed.
  
  
  RESULTS
  At a concentration of 9 microg/ml, nelfinavir induced death of 90% of HL60, IM9, and Jurkat cells. At the same concentration and treatment conditions, less than 10% of aspirated human bone marrow cells showed nelfinavir-induced cell damage. Nelfinavir-induced death of leukemia cells was accompanied by activation of caspases 3, 7, and 8. Despite caspase activation, the upregulation of the anti-apoptotic bcl-2 family member protein mcl-1 that resulted from nelfinavir treatment stabilized the mitochondrial membrane potential, resulting in primarily mitochondria-independent cell death. Pharmacological downregulation of mcl-1 expression by treatment with sorafenib (2 microg/ml) significantly enhanced nelfinavir-induced apoptosis even at lower nelfinavir concentrations (5 microg/ml), but did not have additional detrimental effects on non-malignant bone marrow cells.
  
  
  CONCLUSIONS
  The ability of nelfinavir to induce apoptosis in leukemia cells as a single agent in a mitochondria-independent manner might suggest it could be used as a second or third line of treatment for leukemia patients for whom standard mitochondria-directed treatment strategies have failed. Combination treatment with nelfinavir and sorafenib might further enhance the efficacy of nelfinavir even on chemo-resistant leukemia cells.
authors.affiliation: Ludwig-Maximilians University Munich, Department of Obstetrics/Gynaecology, Molecular Biology Laboratory, Munich, Germany. ansgar.bruening@med.uni-muenchen.de
authors.forename: Ansgar
authors.initials: A
authors.lastname: Brüning
authors.forename: Martina
authors.initials: M
authors.lastname: Rahmeh
authors.forename: Andrea
authors.initials: A
authors.lastname: Gingelmaier
authors.forename: Klaus
authors.initials: K
authors.lastname: Friese
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001557:Benzenesulfonates / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000187:drug effects; D016203:CDC2 Protein Kinase / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D019926:Cyclin B / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D007938:Leukemia / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D051336:Mitochondrial Membranes / Q000187:drug effects*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019888:Nelfinavir / Q000494:pharmacology*; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D000077157:Sorafenib; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D001557:Benzenesulfonates; D019926:Cyclin B; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010671:Phenylurea Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib; D016203:CDC2 Protein Kinase; D053181:Caspase 8; D019888:Nelfinavir