Glioma progression is suppressed by Naringenin and APO2L combination therapy via the activation of apoptosis in vitro an
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PRECLINICAL STUDIES
Glioma progression is suppressed by Naringenin and APO2L combination therapy via the activation of apoptosis in vitro and in vivo Tao Song 1 & Mingyu Zhang 1 & Jun Wu 1 & Fenghua Chen 1 & Ying Wang 1 & Yujie Ma 1 & Zhijie Dai 2 Received: 24 May 2020 / Accepted: 31 July 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Summary Naringenin (NG) is a natural antioxidant flavonoid which is isolated from citrus fruits, and has been reported to inhibit colon cancer proliferation. However, the effects of NG treatment on glioma remain to be elucidated. The present study aimed to explore the effects of NG on glioma in vitro and in vivo. Also, the interactions between NG and APO2 ligand (APO2L; also known as tumor necrosis factor-related apoptosis-inducing ligand) were investigated in glioma. A synergistic effect of NG and APO2L combination on apoptotic induction was observed, though glioma cells were insensitive to APO2L alone. After NG treatment, glioma cells resumed the sensitivity to APO2L and cell apoptosis was induced via the activation of caspases, elevation of decoy receptors 4 and 5 (DR4 and DR5) and induction of p53. Coadministration of NG and APO2L decreased levels of anti-apoptotic B cell lymphoma 2 (Bcl-2) family members Bcl-2 and Bcl-extra large (Bcl-xL), while increased levels of proapoptotic factors Bcl2-associated agonist of cell death (Bad) and Bcl-2 antagonist/killer 1 (Bak). Furthermore, an in vivo mouse xenograft model demonstrated that NG and APO2L cotreatment markedly suppressed glioma growth by activating apoptosis in tumor tissues when compared with NG or APO2L monotherapy. The present study provides a novel therapeutic strategy for glioma by potentiating APO2L-induced apoptosis via the combination with NG in glioma tumor cells. Keywords Glioma . Naringenin . APO2L . Apoptosis
Introduction Glioma is an aggressive type of brain tumor typically associated with poor prognosis, deteriorated life quality and low survival rates, which is considered challenging to treat [1, 2]. According to the World Health Organization (WHO), glioma is classified into different categories, varying from low-grade (slowly-growing) to high-grade (rapidly-growing) depending on its proliferative capacity and invasiveness. The glioblastoma multiforme (GBM, WHO grade IV) is the most malignant form [3–5]. Glioma cells have a marked ability to infiltrate and
* Zhijie Dai [email protected] 1
Department of Neurosurgery, Xiangya Hospital of Central South University, Changsha 410008, Hunan, China
2
Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital of Central South University, 139 Renmin Middle Road, Changsha 410011, Hunan, China
migrate, which enables them to escape surgical resection, radiation exposure and chemotherapy [6]. GBM, the most common and malignant primary intracranial tumor, accounts for ~60% of glioma cases in adults [7]. It invades surrounding brain tissue and quickly develops resistance t
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