Spautin-1, a novel autophagy inhibitor, enhances imatinib-induced apoptosis in chronic myeloid leukemia

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 pro-apoptotic 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.