title: Arsenic trioxide synergistically potentiates the cytotoxic effect of fludarabine in chronic lymphocytic leukemia cells by further inactivating the Akt and ERK signaling pathways.
abstract: CLL remains an incurable disease, making it crucial to continue searching for new therapies efficient in all CLL cases. We have studied the effect of combining arsenic trioxide (ATO) with fludarabine, a frontline drug in CLL. We have found a synergistic interaction between 1 μM ATO and 5 μM fludarabine that significantly enhanced the cytotoxic effect of the individual drugs. Importantly, ATO sensitized fludarabine-resistant cells to the action of this drug. The mechanism behind this effect included the downregulation of phospho-Akt, phospho-ERK, and the Mcl-1/Bim and Bcl-2/Bax ratios. The combination of ATO and fludarabine partially overcame the survival effect induced by co-culturing CLL cells with stromal cells. Therefore, low concentrations of ATO combined with fludarabine may be an efficient therapeutic strategy in CLL patients.
authors: Molecular Cytogenetics Unit, Hematology Department, Hospital Universitario Puerta de Hierro-Majadahonda and IDIPHIM, Madrid, Spain.
authors: Carol
authors: C
authors: Lozano-Santos
authors: Cellular and Molecular Medicine Department, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain.
authors: Irene
authors: I
authors: Amigo-Jiménez
authors: Molecular Cytogenetics Unit, Hematology Department, Hospital Universitario Puerta de Hierro-Majadahonda and IDIPHIM, Madrid, Spain.
authors: Sara
authors: S
authors: Nova-Gurumeta
authors: Molecular Cytogenetics Unit, Hematology Department, Hospital Universitario Puerta de Hierro-Majadahonda and IDIPHIM, Madrid, Spain.
authors: Nuria
authors: N
authors: Pérez-Sanz
authors: Cellular and Molecular Medicine Department, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain. Electronic address: agarciapardo@cib.csic.es.
authors: Angeles
authors: A
authors: García-Pardo
authors: Molecular Cytogenetics Unit, Hematology Department, Hospital Universitario Puerta de Hierro-Majadahonda and IDIPHIM, Madrid, Spain. Electronic address: jagarciam@aehh.org.
authors: José A
authors: JA
authors: García-Marco
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology / Q000627:therapeutic use*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006131:Growth Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D010087:Oxides / Q000494:pharmacology / Q000627:therapeutic use*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D004791:Enzyme Inhibitors; D006131:Growth Inhibitors; D010087:Oxides; D051057:Proto-Oncogene Proteins c-akt; D014740:Vidarabine; C024352:fludarabine; D000077237:Arsenic Trioxide
keywords: Arsenic trioxide; CLL; Combined therapies; Fludarabine; Survival pathways; Synergistic effect