Trisenox induces cytotoxicity through phosphorylation of mitogen-activated protein kinase molecules in acute leukemia...

Trisenox (TX) has been used successfully for the treatment of acute promyelocytic leukemia (APL) patients. TX-induced cytotoxicity in APL cells remains poorly understood. In this study, we investigated the molecular mechanism of TX cytotoxicity using APL cell lines. We assessed TX toxicity by quantitatively measuring lactate dehydrogenase levels. Inhibition of cell cycle progression was assessed by confocal microscopy of Ki-67 expression. Apoptosis was evaluated by Western blot analysis of apoptotic proteins expression, immunocytochemistry, and confocal imaging of annexin V and propidium iodide. Mitogen-activated protein kinase (MAPK) signaling cascade was analyzed by Western blot analysis and inhibitor-based experiments with APL cells. We found that TX-induced cytotoxicity inhibited APL cell cycle progression. TX also induced significant (P < 0.05) changes in the expression levels of apoptotic molecules and activated the phosphorylation of MAPK signaling pathways in APL cells. Understanding the mechanism of TX cytotoxicity would be helpful in the design of new APL drugs.