title: The mechanism of synergistic effects of arsenic trioxide and rapamycin in acute myeloid leukemia cell lines lacking typical t(15;17) translocation.
abstract: Arsenic trioxide (ATO) has potent clinical activity in the treatment of patients with acute promyelocytic leukemia (APL), but is much less efficacious in acute myeloid leukemia (AML) lacking t(15;17) translocation. Recent studies have indicated that the addition of mammalian target of rapamycin (mTOR) inhibitors may increase the sensitivity of malignant cells to ATO. The aim of the present study was to test for possible synergistic effects of ATO and rapamycin at therapeutically achievable doses in non-APL AML cells. In HL-60 and U937 cell lines, the inhibitory effects of low concentrations of ATO and rapamycin were synergistic and more pronounced in U937 cells. The combination of drugs increased apoptosis in HL-60 cells and increased the percentage of cells in G(0)/G(1) phase in both cell lines. In U937 cells, rapamycin alone increased the activity of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and the addition of ATO decreased the level of phosphorylated ERK, Ser473 phosphorylated Akt and anti-apoptotic Mcl-1 protein. Primary AML cells show high sensitivity to growth-inhibitory effects of rapamycin alone or in combination with ATO. The results of the present study reveal the mechanism of the synergistic effects of two drugs at therapeutically achievable doses in non-APL AML cells.
authors.affiliation: Department of Physiology and Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Salata 3, POB 978, 10 000, Zagreb, Croatia.
authors.forename: Vilma
authors.initials: V
authors.lastname: Dembitz
authors.forename: Hrvoje
authors.initials: H
authors.lastname: Lalic
authors.forename: Alen
authors.initials: A
authors.lastname: Ostojic
authors.forename: Radovan
authors.initials: R
authors.lastname: Vrhovac
authors.forename: Hrvoje
authors.initials: H
authors.lastname: Banfic
authors.forename: Dora
authors.initials: D
authors.lastname: Visnjic
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002884:Chromosomes, Human, Pair 15; D002886:Chromosomes, Human, Pair 17; D004357:Drug Synergism; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014178:Translocation, Genetic
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; D058570:TOR Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D000077237:Arsenic Trioxide; D020123:Sirolimus