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Abstract
Imatinib mesylate (IM), a targeted competitive inhibitor of the BCR-ABL tyrosine kinase, has revolutionized the clinical treatment of chronic myeloid leukemia (CML). However, resistance and intolerance are still a challenge in the treatment of CML. Autophagy has been proposed to play a role in IM resistance. To investigate the anti-leukemic activity of specific and potent autophagy inhibitor-1 (spautin-1) in CML, we detected its synergistic effect with IM in K562 and CML cells. Our results showed that spautin-1 markedly inhibited IM-induced autophagy in CML cells by downregulating Beclin-1. Spautin-1 enhanced IM-induced CML cell apoptosis by reducing the expression of the anti-apoptotic proteins Mcl-1 and Bcl-2. We further demonstrated that the proapoptotic activity of spautin-1 was associated with activation of GSK3β, an important downstream effector of PI3K/AKT. The findings indicate that the autophagy inhibitor spautin-1 enhances IM-induced apoptosis by inactivating PI3K/AKT and activating downstream GSK3β, leading to downregulation of Mcl-1 and Bcl-2, which represents a promising approach to improve the efficacy of IM in the treatment of patients with CML.
Highlights
Chronic myeloid leukemia (CML) is a hematological malignancy characterized by the presence of the Philadelphia chromosome [1]
The results showed that spautin-1 markedly attenuated the protein levels of Beclin-1 induced by imatinib mesylate (IM), but had no significant effect on other autophagy factors (Fig. 1B and C)
CML cells may respond to IM in a variety of ways ranging from initiation of cell death to the activation of survival pathways such as autophagy [7,20,21]
Summary
Chronic myeloid leukemia (CML) is a hematological malignancy characterized by the presence of the Philadelphia chromosome [1]. This chimeric chromosome generates the fusion gene BCR-ABL, produces fusion proteins and leads to constitutive activation of the tyrosine kinase (TK). Treatment of CML was revolutionized by the advent of imatinib mesylate (IM), a targeted agent which inhibits the activity of BCR-ABL [4]. IM has dramatically improved the prognosis of CML patients in chronic phase. Patients in advanced stage (blast crisis) manifest drug resistance against IM, leading to relapse, due to amplification of BCR-ABL and the acquisition of BCR-ABL-independent mechanisms [5]
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