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The combination of arsenic trioxide and rapamycin has potent inhibitory effects on acute myeloid leukemia (AML) cells.

13101 Background: Arsenic trioxide (As2O3) exhibits potent growth inhibitory and pro-apoptotic effects against a variety of neoplastic cells, but the precise mechanisms by which it mediates such effects are not known. The mammalian target of rapamycin (mTOR) is a key cellular regulator of multiple signaling events that control initiation of mRNA translation in leukemia cells. We examined the effects of As2O3 on the activation of mTOR-dependent pathways that regulate initiation of mRNA translation in acute myeloid leukemia (AML) cells. We also determined the effects of the combination of As2O3 with the mTOR inhibitor rapamycin on the growth of AML cell lines.


METHODS
The human leukemia cell lines, KG-1, U937, and MM6, were incubated and cultured with increasing concentrations of As2O3, in the presence or absence of the mTOR inhibitor rapamycin. Cell lysates were immunoprecipitated with an anti-p70 S6 kinase antibody, and immune-complex kinase assays to detect p70 S6 kinase activity were performed. In addition, cell proliferation assays were carried out in cells treated with or without rapamycin (10 or 20 nM) and increasing concentrations of AS2O3 (0 to 5 uM).


RESULTS
As2O3-treatment of U937 cells resulted in strong induction of p70 S6 kinase activity, which was inhibited by concomitant treatment of cells with rapamycin. In cell proliferation assays, we found that rapamycin alone significantly inhibited the growth of U937, KG-1, and MM6 cells. The addition of As2O3 further enhanced the inhibitory effects of rapamycin, in a dose-dependent manner, indicating that the combination of these agents is more potent in inhibiting the growth of AML cell lines than each agent alone.


CONCLUSIONS
During treatment of AML cell lines with As2O3, the p70 S6 kinase pathway is activated, apparently in a negative feedback regulatory manner. Pharmacological inhibition of mTOR with rapamycin has potent antileukemic properties, which are further enhanced by As2O3. Therefore, the use of As2O3 and rapamycin in combination may be a promising strategy for the treatment of AML. No significant financial relationships to disclose.