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

Shao,Shan; Li,Su; Qin,Youwen; Wang,Xiaorui; Yang,Yining; Bai,Haitao; Zhou,Lili; Zhao,Chuxian; Wang,Chun

doi:10.3892/ijo.2014.2313

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

Authors:
- Shan Shao
- Su Li
- Youwen Qin
- Xiaorui Wang
- Yining Yang
- Haitao Bai
- Lili Zhou
- Chuxian Zhao
- Chun Wang
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Affiliations: Department of Hematology, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai 200080, P.R. China
Published online on: February 27, 2014 https://doi.org/10.3892/ijo.2014.2313
Pages: 1661-1668

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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 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.

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