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N1-guanyl-1,7-diaminoheptane enhances the chemosensitivity of acute lymphoblastic leukemia cells to vincristine through inhibition of eif5a-2 activation

Liu, Yanhuia,*; Xue, Feib,*; Zhang, Yina; Lei, Pingchonga; Wang, Zhena; Zhu, Zunmina; Sun, Kaia

doi: 10.1097/CAD.0000000000000550
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N1-guanyl-1,7-diaminoheptane (GC7), a deoxyhypusine synthase inhibitor, has been shown to exert antiproliferation effects in many solid tumors by regulating eukaryotic translation initiation factor 5a2 (eif5a-2). However, little is known about the role of GC7 and eif5a-2 in drug resistance in acute lymphoblastic leukemia (ALL). In the present study, we investigated the effect of GC7 on drug-resistant ALL and its potential mechanism. We found that using the CCK-8 assay that combined treatment with GC7 and vincristine (VCR) significantly inhibited the cell viability of two ALL cell lines. Using EdU incorporation assays and flow cytometry, we also showed that GC7 could markedly enhance the VCR sensitivity of ALL cells by suppressing cell proliferation and promoting apoptosis. Furthermore, we showed that GC7 could downregulate eif5a-2 and myeloid cell leukemia-1 (Mcl-1) expression. Knockdown of eif5a-2 inhibited the expression of Mcl-1 and significantly enhanced the VCR sensitivity. Moreover, eif5a-2 knockdown decreased the regulatory role of GC7 in increasing VCR sensitivity. Thus, our findings indicate that combined treatment with GC7 could enhance VCR sensitivity of ALL cells by regulating the eif5a-2/Mcl-1 axis. Together, our results highlight the potential clinical application of GC7 in VCR-based chemotherapy for the treatment of ALL.

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Departments of aHemotology

bHepatobiliary and Pancreatic Surgery, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou, People’s Republic of China

*Yanhui Liu and Fei Xue contributed equally to the writing of this article.

Correspondence to Yanhui Liu, PhD, Department of Hemotology, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, NO7, Weiwu Road, 450003 Zhengzhou, People’s Republic of China Tel: +86 371 6558 0120; fax: +86 371 6596 4376; e-mail: jingsanlu66@163.com

Received November 7, 2016

Accepted July 17, 2017

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