The mechanism of synergistic effects of arsenic trioxide and rapamycin in acute myeloid leukemia cell lines lacking typical t(15;17) translocation

Scientific paper - Original scientific paper

• Author: Vilma Dembitz
• Author: Hrvoje Lalić
• Author: Alen Ostojić
• Author: Radovan Vrhovac
• Author: Hrvoje Banfić
• Author: Dora Višnjić
• Author's institution: University of Zagreb; School of Medicine
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Clinical Medical Sciences

Abstract (english)

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.

• Keywords (english): Aged; Antineoplastic Agents/pharmacology; Apoptosis/drug effects; Arsenicals/pharmacology; Cell Cycle/drug effects; Cell Line, Tumor; Cell Survival/drug effects; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; Drug Synergism; Female; HL-60 Cells; Humans; Leukemia, Myeloid, Acute/drug therapy; Leukemia, Myeloid, Acute/genetics; Leukemia, Myeloid, Acute/metabolism; Male; Middle Aged; Mitogen-Activated Protein Kinases/metabolism; Oxides/pharmacology; Signal Transduction/drug effects; Sirolimus/pharmacology; TOR Serine-Threonine Kinases/metabolism; Translocation, Genetic
• Language: english
• Publication type: Scientific paper - Original scientific paper
• Publication status: Published
• Peer review: Peer review
• Publication version: Accepted version
• Journal title: International Journal of Hematology
• Numbering: vol. 102, no. 1, pp. 12-24
• p-ISSN: 0925-5710
• DOI: https://doi.org/10.1007/s12185-015-1776-2
• URN:NBN: urn:nbn:hr:105:118218
• Publication: 2015-07
• Document URL: https://doi.org/10.1007/s12185-015-1776-2
• Type of resource: Text
• Access conditions: Open access
• Created on: 2024-03-28 08:54:53