Rapamycin enhances dimethyl sulfoxide-mediated growth arrest in human myelogenous leukemia cells (CROSBI ID 578519)
Prilog sa skupa u zborniku | sažetak izlaganja sa skupa | međunarodna recenzija
Podaci o odgovornosti
Lalić, Hrvoje ; Lukinović-Škudar, Vesna ; Banfić, Hrvoje ; Višnjić, Dora
engleski
Rapamycin enhances dimethyl sulfoxide-mediated growth arrest in human myelogenous leukemia cells
Aim: The pharmacological inhibitors of phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway have been proposed in the treatment of leukemia based on their antiproliferative effects, but their possible role in differentiation therapy is less explored. Rapamycin, an mTOR-inhibitor, has been recently reported to potentiate all-trans retinoic acid-mediated differentiation of HL-60 and NB4 cell lines along granulocytic pathway, and monocytic differentiation of U937 cells induced by vitamin D3. Dimethyl sulfoxide (DMSO) is a potent inducer of granulocytic differentiation of myeloid cell lines and erythroid differentiation of K562 cells. The aim of the present study was to test for the possible synergistic effects of rapamycin and DMSO on growth arrest and differentiaton of human myelogenous leukemia cells. Materials and Methods: Myeloblastic (AML-M2) HL-60, promyelocytic (AML-M3) NB4, monocytic (AML-M5) U937, immature (AML-M6) KG-1, and erythro-megakaryocytic K562 cell lines were maintained in exponential growth and differentiated in the presence of DMSO (0.6 or 1.25%). The number of viable cells was quantified using a hemocytometer and trypan blue exclusion. The expression of differentiation markers and the cell cycle distribution of propidium iodide-labeled cells were determined by FACS analyses. Cell morphology was evaluated on May-Grunwald-Giemsa-stained cytospin preparations. The level of phosphorylated (Thr389) and total p70 S6 Kinase (p70 S6K) in total cell lysates was determined by Western blot analysis. Results: Western blot analysis demonstrated that the incubation of leukemia cells in the presence of 20 nM rapamycin for 20 min completely reduced the level of Thr389-phosphorylated p70 S6K, which is one of the principle downstream targets of activated mTOR. When applied at the same dose for 96 h, rapamycin alone exerted minimal antiproliferative effects ; significant decrease in the number of viable cells was observed in rapamycin-treated HL-60 and KG-1 cells. The presence of 1.25% DMSO for 96 h significantly inhibited the growth of all cell lines tested, and the combination of rapamycin and DMSO inhibited the number of viable cells significantly more than either agent alone. FACS analysis of propidium iodide-labeled cells revealed a synergistic effect of rapamycin and DMSO on cell cycle arrest in G0/G1 phase. Conclusion: Rapamycin potentiates growth-inhibitory effects of DMSO in the established acute myeloid leukemia lines. These results suggest that mTOR inhibitors may have beneficial effects in combination with differentiation agents in therapy of AML.
rapamycin; DMSO; leukemia
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Podaci o prilogu
87-87.
2011.
nije evidentirano
objavljeno
Podaci o matičnoj publikaciji
Liječnički vjesnik
Zagreb:
1330-49257
Podaci o skupu
Leukemia and Lymphoma East and West are Together
poster
17.09.2011-21.09.2011
Dubrovnik, Hrvatska