Comparative proteome study of apoptosis induced by As4S4 in retinoid acid resistant human acute promyelocytic leukemia NB4-R1 cells.

Tetra-arsenic tetra-sulfide (As(4)S(4)), with improved toxicity profiles relative to arsenic trioxide, is the essential component of the new oral arsenic formulation which is highly effective and safe in the treatment of both newly diagnosed acute promyelocytic leukemia (APL) and more importantly relapsed/refractory APL. Although it is investigated that the therapeutic action of As(4)S(4) is closely associated with its induced cells apoptosis, the definitive systematic molecular mechanism of action of As(4)S(4) in APL therapy is still remained unknown. In this study, a serial of assays in vitro about the cytotoxicity of As(4)S(4) and cellular apoptotic evidences were done, then a proteomic investigation with the high-resolution two-dimensional electrophoresis system and mass spectrometry were performed to obtain for the first time systematic identification and characterization of the global proteome of apoptosis induced by As(4)S(4) in retinoic acid (RA)-resistant cells. Among them, expressional and functional regulations of target proteins SET, RPP2 and PHB might be the potential novel effective therapeutic strategies for RA-resistant APL. This study will not only facilitate to understand the signal transduction of apoptosis of RA-resistant APL cells induced by As(4)S(4) as a whole, but also is important to screen for drug targets as a new therapeutic strategy for hematopoietic malignant tumors.