Abstract
Arsenic trioxide (As203) is effective for the patients with relapsed acute promyelocytic leukemia (APL); however, possible adverse effects of this new anti-leukemic drug are highly important issue related to its clinical use. To resolve this problem, we here investigated in vitro and in vivo, the effects of the combination of AS203 and GM-CSF as a novel therapeutic approach for the treatment of APL. Treatment of both retinoic acid (RA)-sensi- tive and -resistant APL cell lines (NB4 and UF-1 cells, respectively) with the combination of AS203 and GM-CSF for 4 days resulted in inducing differentiation, but not apoptosis, to mature granulocytes. In addition, the combination of both agents induced degradation of PML/RARα protein. While GM-CSF did not affect the expression of Bcl-2, it decreased the levels of Bax protein in As203-treated cells. In addition, both chemicals increased the levels of Mcl-1 in APL cells. A specific inhibitor of Jak2, AG490, completely blocked the ability of GM-CSF to prevent apoptosis and induce differentiation of As203-treated UF-1 cells. In in vivo analysis, As203 decreased the size of tumors in an RA-resistant APL model of human GM-CSF-producing transgenic SCID mice that had a high level of human GM-CSF in their sera. Moreover, diminished tumors showed mature granulocytes, indicating that As203 in combination with GM-CSF also induced differentiation of APL cells in vivo. In conclusion, the combination of As203 and GM-CSF would be a novel differentiation- inducing therapy in patients with APL.
Published Version
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