Mechanism of action of all-trans retinoic acid and arsenic trioxide in the treatment of acute promyelocytic leukemia.

Treatment of APL with ATRA or As2O3 alone or in combination with chemotherapy yields a complete remission as high as 85%-95%, but their mechanisms of action remain unclear. The mechanisms of action underlying ATRA treatment are (1) relocalization of the PML restoration of normal structure of nuclear bodies and degradation of PML-RAR alpha protein via caspase-mediated cleavage and proteosome-dependent degradation; (2) conversion of PML-RAR alpha from a transcription repressor (CoR) to a transcription activator (CoA) under therapeutic concentration of ATRA (3) coordinated genes expression induced by ATRA resulting in an elegant and intricate cellular program for the commitment to differentiation. 169 genes were modulated to express, with 100 genes up-regulated and 69 down-regulated. As2O3 exerts its action by dual dose-dependent manner. At higher concentration (1-2 microns/l), it induces apoptosis of the leukemic cells associated with disruption of mitochondrial membrane potential, elevation of caspase-3 and other caspases activity and decline of Bcl-2 expression. At lower concentration (0.1-0.5 micron/l), it triggers differentiation with elevation of CD11b expression accompanied by morphologically partial differentiation. At both concentrations, As2O3 causes degradation of PML-RAR alpha protein implicated probably in its mechanisms of action.