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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.

Author information

1
Neuroscience Research Center, Department of Neurology, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran.
2
Department of Neuroscience, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran. n-vousooghi@tums.ac.ir.
3
Genetics Laboratory, Iranian National Center for Addiction Studies (INCAS), Tehran University of Medical Sciences, Tehran, Iran. n-vousooghi@tums.ac.ir.
4
Research Center for Cognitive and Behavioral Sciences, Tehran University of Medical Sciences, Tehran, Iran. n-vousooghi@tums.ac.ir.
5
Department of Human Nutritional Sciences, University of Manitoba, Winnipeg, MB, Canada.
6
Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran. mt.joghataei@yahoo.com.
7
Neuroscience Department, School of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran. mt.joghataei@yahoo.com.

Abstract

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.

KEYWORDS:

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

PMID:
28616662
DOI:
10.1007/s10495-017-1382-2
[Indexed for MEDLINE]

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