Identification of imatinib mesylate as a potent inhibitor of the Abl kinase and the subsequent findings that this compound displays
growth inhibitory and pro-apoptotic effects in Bcr-Abl+ cells, has deeply conditioned CML treatment. Unfortunately the initial
striking efficacy of this drug has been overshadowed by the development of clinical resistance. A wide variety of molecular mechanisms
can underlie such resistance mechanisms. In the recent years, heme oxygenase-1 (HO-1) expression has been reported as an important
protective endogenous mechanism against physical, chemical and biological stress and this cytoprotective role has already been demonstrated
for several solid tumors and acute leukemias. The aim of the present study was to investigate the effect of HO-1 expression on cell
proliferation and apoptosis in chronic myeloid leukemia cells, K562 and LAMA-84 cell lines following imatinib treatment. Cells were
incubated for 24h with Imatinib (1μM) alone or in combination with Hemin (10μM), an inducer of HO-1. In addition, cells were also
treated with HO byproducts, bilirubin and carbon monoxide (CO), or with a protease inhibitor (Ed64) to inhibit HO-1 nuclear translocation.
Pharmacological induction of HO-1 was able to overcome the effect of imatinib. The cytoprotective effect of HO-1 was further confirmed
after silencing HO-1 by siRNA. Interestingly, neither bilirubin nor CO was able to protect cells from Imatinib-induced toxicity.
By contrast, the protective effect of HO-1 was mitigated by the addition of E64d, preventing HO-1 nuclear translocation. Finally,
imatinib was able to increase the formation of cellular reactive oxygen species (ROS) and this effect was reversed by HO-1 induction or
the addition of N-acetylcisteine (NAC). In conclusion, the protective effect of HO-1 on imatinib-induced cytotoxicity does not involve its
enzymatic byproducts, but rather the nuclear translocation of HO-1 following proteolytic cleavage.