title: BRAF signals to pro-apoptotic BIM to enhance AraC cytotoxicity induced in AML cells by Vitamin D-based differentiation agents.
abstract: Vitamin D has so far not fulfilled its early promise as an antineoplastic agent, in spite of compelling in vitro data. With the aim of bringing vitamin D or its derivatives (VDDs) effectively to the clinic, we developed a two-pronged approach. First, by adding the plant-derived Carnosic Acid (CA) to a vitamin D2 derivative Doxercalciferol we increased its differentiation potency without increasing it hypercalcemic properties. Second, we added these two agents together to AML cells already treated with Cytarabine (AraC), the standard drug for the treatment of patients with AML. We now report that BRAF, a part of the MAPK signaling pathway, is required for the optimally increased cell death in this system and acts upstream of BIM, the regulator of the caspase cascade that leads to cell death by apoptosis. It is proposed that this therapeutic regimen should be tested in a clinical trial.
authors.affiliation: Department of Pathology & Laboratory Medicine, NJ Medical School, Rutgers, 185 South Orange Ave., Newark, NJ 07103, United States.
authors.forename: Xuening
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Medicine, University of Connecticut, Farmington, CT 06030, United States.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Harrison
authors.affiliation: Department of Pathology & Laboratory Medicine, NJ Medical School, Rutgers, 185 South Orange Ave., Newark, NJ 07103, United States. Electronic address: studzins@njms.rutgers.edu.
authors.forename: George P
authors.initials: GP
authors.lastname: Studzinski
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D000072224:Bcl-2-Like Protein 11 / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003561:Cytarabine / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014807:Vitamin D / Q000031:analogs & derivatives / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D000072224:Bcl-2-Like Protein 11; D003561:Cytarabine; D014807:Vitamin D; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: AML; Apoptosis; BIM; BRAF; Cytarabine; Vitamin D