Glutathione-S-transferase pi inhibits As2O3-induced apoptosis in lymphoma cells: involvement of hydrogen peroxide catabolism.

Arsenic trioxide (As(2)O(3)) is an effective agent for the treatment of relapsed and refractory acute promyelocytic leukemia by induction of partial differentiation and apoptosis. As(2)O(3), at therapeutic concentrations (1-2 microM), induced apoptosis in Raji lymphoma cells but not in Jurkat lymphoma cells, which inversely correlated with the levels of glutathione-S-transferase pi (GSTP1), but not GSTpi(1) and GSTM(1), expression and activity. GSTP1 mRNA, protein level, and activity were high in Jurkat cells but undetectable in Raji cells. Stable transfection of GSTP1 into Raji cells decreased the amount of As(2)O(3)-induced apoptosis. Apoptosis induced by therapeutic concentrations of As(2)O(3) in Raji cells is related to increasing H(2)O(2) intracellular accumulation but not to JNK activation. Forced expression of GSTP1 by transfection of Raji cells significantly decreased the basal amount of H(2)O(2) and its levels after therapeutic concentration of As(2)O(3) treatment. Added exogenous H(2)O(2) was removed more rapidly, which correlated with a greater decrease in reduced glutathione level in Raji clones expressing GSTP1 than in those clones without GSTP1 expression. Overexpression of GSTP1 in transfected Raji clones was also found to decrease the retention of As(2)O(3). These data suggest that GSTP1 blocks As(2)O(3)-induced apoptosis in lymphoma cells by decreasing intracellular amounts of H(2)O(2) by catabolism and H(2)O(2) production by decreasing the intracellular retention of As(2)O(3).