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Antiproliferative effects of arsenic trioxide on leukemia cells are enhanced by rapamycin and all-trans-retinoic acid

INTRODUCTION: All-trans-retinoic acid (ATRA) and arsenic trioxide (As2O3) are clinically used in the treatment of acute promyelocytic leukemia (APL), a subtype of acute myeloid leukemia (AML) characterized by translocation t(15 ; 17). Both substances have also shown some promising results on other types of AML in vitro, but those results have either been disputed by clinical trials or the tested doses were too high to be used clinically without serious toxicity. METHODS: In this study, we investigated whether addition of rapamycin, inhibitor of mTOR kinase, enhances the effects of ATRA and As2O3 on AML cell lines. Furthermore, we tested possible synergistic effect of combination of ATRA and As2O3 on given cell lines. NB4, HL60, U937, KG-1 and K562 cells were incubated with ATRA, two doses of As2O3, rapamycin and their combination. Cell proliferation was quantified by determining the number of viable cells with hemocytometer. The surface expression of CD11b was used as marker of cell differentiation and it was determined by flow cytometric analysis. The initial activity of mTOR kinase in each cell line was measured with western blot analysis of level of phosphorilated p70 S6 kinase. RESULTS: Rapamycin potentiates antiproliferative effects of lower doses of As2O3 in all non-APL AML cells without affecting their differentiation. The correlation between the initial activity of mTOR and the reactivity on As2O3 and rapamycin is not clear. Rapamycin also increased ATRA-induced differentiation of HL60 and U937 cells. Combination of ATRA and As2O3 was the most efficient in reducing cell number and inducing differentiation in cell lines tested. CONCLUSION: Our study demonstrated that combination of rapamycin and lower doses of arsenic trioxide as well as combination of all-trans-retinoic acid and arsenic trioxide may have a role in treatment of AML that lack typical t(15 ; 17) translocation.

acute myeloid leukemia; all-trans-retinoic acid; arsenic trioxide; rapamycin; cell proliferation

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