Mechanisms of apoptosis and differentiation induced by arsenic trioxide in leukemic cells and its clinical application

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Arsenic trioxide effectively induces clinical remission via apoptosis in relapsed acute promyelocytic leukemia (APL). However, its molecular mechniams od inducing apoptosis is still unclear. In addition, this new anti-leukemic drug is considered to be a poison, its possible adverse effects are a highly important issue related to its clinical use. Arsenic trioxide can induce apoptosis of both retinoic acid-sensitive NB4 and-resistant UF-1 cells with down-regulation of Bcl-2 and up-regulation of Bax proteins, respectively. Also, arsenic trioxide degrades APL-specific PML/RARα fusion protein. Interestingly, a combination of arsenic trioxide and GM-CSF induces differentiation, but not apoptosis of APL cells. GM-CSF was found to be associated with increased tyrosine phosphorylation of Jak2 kinase in both NB4 and UF-1 cells. A specific inhibitor of Jak2, AG490, completely blocked the ability of GM-CSF to prevent apoptosis and induce differentiation of arsenic trioxide-treated APL cells, suggesting that Jak/STAT pathway is dritical for the anti-apoptotic activity of GM-CSF in APL cells treated with both agents. These results are also observed in vivo by using human GM-CSF-producing transgenic SCID mice model. In conclusion, a combination of arsenic trioxide and GM-CSF appears to be a novel differentiation-inducing therapy in patients with APL.Further molecular studies to determine the target molecules of arsenic trioxide will be needed.