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Apoptosis. 2017 Aug;22(8):1025-1034. doi: 10.1007/s10495-017-1382-2.

Perifosine enhances bevacizumab-induced apoptosis and therapeutic efficacy by targeting PI3K/AKT pathway in a glioblastoma heterotopic model.

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Neuroscience Research Center, Department of Neurology, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran.
Department of Neuroscience, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Genetics Laboratory, Iranian National Center for Addiction Studies (INCAS), Tehran University of Medical Sciences, Tehran, Iran.
Research Center for Cognitive and Behavioral Sciences, Tehran University of Medical Sciences, Tehran, Iran.
Department of Human Nutritional Sciences, University of Manitoba, Winnipeg, MB, Canada.
Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran.
Neuroscience Department, School of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran.


Bevacizumab (BVZ) as an antiangiogenesis therapy leads to a transient therapeutic efficacy in high-grade glioma. However, the proapoptotic potential of BVZ has not been well elucidated, yet. There is also a tumor resistance to BVZ that is linked to post-treatment metalloproteinases and AKT activities. Herein, the association between therapeutic efficacy and putative proapoptotic activity of low-dose BVZ either alone or in combination with a specific inhibitor of AKT called perifosine (PRF), in a glioma model was investigated. BALB/c mice bearing C6 glioma tumor were treated with BVZ and PRF either alone or combined for 13 days (nā€‰=ā€‰11/group). At the end of treatments, apoptosis, proliferation and vascular density, in the xenografts (3/group) were detected by TUNEL staining, Ki67 and CD31 markers, respectively. Relative levels of cleaved-caspase3, phospho-AKT (Ser473) and matrix metalloproteinase2 (MMP2) were measured using western blotting. PRF and BVZ separately slowed down tumor growth along with the cell apoptosis induction associated with a profound increase in caspase3 activity through an AKT inhibition-related pathway for PRF but not BVZ. Unlike PRF, BVZ significantly increased the intratumor MMP2 and phospho-AKT (Ser473) levels coupled with the slight antiproliferative and significant antivascular effects. Co-administration of PRF and BVZ versus monotherapies potentiated the proapoptotic effects and reversed the BVZ-induced upregulation of phospho-AKT (Ser473) and MMP2 levels in C6 xenografts, leading to the optimal antiproliferative activity and tumor growth regression and longer survival. In conclusion, BVZ plus PRF renders a paramount proapoptotic effect, leading to a major therapeutic efficacy and might be a new substitute for GBM therapy in the clinic.


AKT signal; Apoptosis; Bevacizumab; C6 heterotopic xenograft; Combination therapy; Glioblastoma multiforme

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