Enhanced Bcr-Abl-specific antileukemic activity of arsenic trioxide through glutathione-depletion in imatinib-resistant cells

In chronic myeloid leukemia (CML), mechanisms of resistance to imatinib mesylate (Glivec), a selective Bcr-Abl kinase inhibitor, have been traced to Bcr-Abl reactivation, most frequently by mutations in the kinase domain of Bcr-Abl, or to BCRABL amplification. Bcr-Abl overexpression not only directly modulates sensitivity to imatinib, it may also indirectly influence treatment response by influencing the rate of mutation development in the kinase domain. We previously demonstrated the ability of arsenic trioxide (As2O3, ATO, Trisenox, Cell Therapeutics, Seattle, USA) to make imatinib resistant cell lines and primary cells susceptible to imatinib-induced growth inhibition and apoptosis. Furthermore, we were able to confirm previous reports that ATO-induced downregulation of Bcr-Abl protein expression leads to reduced total cellular Bcr-Abl activity in imatinib-resistant cell lines that are characterized by Bcr-Abl dependent resistance. Nimmanapalli et al. have traced the mechanism of ATO-dependent Bcr-Abl-suppression to specific inhibition of translation. Given the inverse relationship between glutathione-levels and the antileukemic activity of ATO, we asked whether ATO-activity could be increased by modulation of cellular glutathione (GSH). The effects of GSH-modulation on the antileukemic activity of ATO in CML were studied using dl-buthionine[S,R]-sulfoximine (BSO), a specific and irreversible inhibitior of the rate limiting enzyme in GSH-biosynthesis γ-glutamylcysteine synthetase.