Arsenic trioxide and bortezomib interact synergistically to induce apoptosis in chronic myelogenous leukemia cells resistant to imatinib mesylate through Bcr/Abl-dependent mechanisms

Arsenic trioxide (As2O3) and the proteasome inhibitor bortezomib (BTZ) have been used successfully to treat acute promyelocytic leukemia and multiple myeloma. Their synergistic effects with other anticancer drugs have been widely studied. In this study, interactions between As2O3 and BTZ were examined in imatinib-resistant Bcr/Abl(+) (K562r) cells. Co-treatment of K562r cells with subtoxic concentrations of As2O3 (2 mu M) and BTZ (24 nM) resulted in a synergistic enhancement in growth inhibition and apoptosis, as demonstrated by increased annexin V staining. These events were associated with activation of protein kinase C delta, poly ADP-ribose polymerase cleavage and caspase-3 activation, along with downregulation of Bcr/Abl mRNA and Bcr/Abl protein expression levels during apoptosis. In addition, reactive oxygen species were downregulated during combined treatment in K562r cells. Collectively, these findings suggest that BTZ and As,03 act synergistically to induce apoptosis in K562r cells. Therefore, further studies are required to assess the potential of BTZ and As2O3 combinatory treatment of chronic myeloid leukemia, particularly using imatinib-resistant Bcr/Abl(+) clones.