Heme Oxygenase 1-Induced Resistance to Imatinib In Chronic Myelogenous Leukemia Cells

Abstract

Abstract 4410Heme oxygenase 1 (HO-1) is the rate-limiting enzyme in heme degradation leading to the generation of free iron, biliverdin and carbon monoxide (CO). In this study, K562 cells were incubated for 24 h with imatinib (1 μM) alone or in combination with: 1) cobalt protoporphyrin (CoPP, 10 μM), a potent inducer of HO-1; or 2) tin mesoporphyrin (SnMP, 10 μM), an inhibitor of HO activity. CoPP was able to overcome the inhibitory effect of imatinib while SnMPP restored the cytotoxicity. Interestingly, neither bilirubin nor CO (using the CO-releasing agent CORM-3) were able to protect K562 cells from imatinib-induced toxicity. The protective effect of CoPP was mitigated by addition of a protease inhibitor (Ed64), which was able to stop HO-1 nuclear translocation. We also analyzed 96 kinase genes and found that addition of CoPP in combination with imatinib leads to at least seven kinases being significantly increased while the expression of these genes was reduced in cells treated with imatinib alone or in the presence of SnMP. All of them are able to activate mitogenic signals. We also found that 1 μM imatinib was able to increase the formation of cellular reactive oxygen species and this effect was inhibited by CoPP and restored in presence of SnMP. In conclusion, the protective effect of HO-1 on imatinib-induced cytotoxicity does not involve the action of its catabolites, but rather a translocation of HO-1 to the nucleus after proteolytic cleavage. Migration to the nucleus activates several kinases able to induce mitogenic signals thus enabling HO-1 to reduce oxidative stress induced by imatinib. Disclosures:Di Raimondo:celgene: Honoraria.