title: Inhibition of autophagy induced by quercetin at a late stage enhances cytotoxic effects on glioma cells.
abstract: Glioma is the most common primary brain tumor in the central nervous system (CNS) with high morbidity and mortality in adults. Although standardized comprehensive therapy has been adapted, the prognosis of glioma patients is still frustrating and thus novel therapeutic strategies are urgently in need. Quercetin (Quer), an important flavonoid compound found in many herbs, is shown to be effective in some tumor models including glioma. Recently, it is reported that adequate regulation of autophagy can strengthen cytotoxic effect of anticancer drugs. However, it is not yet fully clear how we should modulate autophagy to achieve a satisfactory therapeutic effect. 3-Methyladenine (3-MA) and Beclin1 short hairpin RNA (shRNA) were used to inhibit the early stage of autophage while chloroquine (CQ) to inhibit the late stage. MTT assay was implemented to determine cell viability. Transmission electron microscopy, western blot, and immunohistochemistry were adopted to evaluate autophagy. Western blot, flow cytometry, and immunohistochemistry were used to detect apoptosis. C6 glioma xenograft models were established to assess the therapeutic effect (the body weight change, the median survival time, and tumor volume) in vivo. Quercetin can inhibit cell viability and induce autophagy of U87 and U251 glioma cells in a dose-dependent manner. Inhibition of early-stage autophagy by 3-MA or shRNA against Beclin1 attenuated the quercetin-induced cytotoxicity. In contrast, suppression of autophagy at a late stage by CQ enhanced the anti-glioma efficiency of quercetin. Therapeutic effect of quercetin for malignant glioma can be strengthened by inhibition of autophagy at a late stage, not initial stage, which may provide a novel opportunity for glioma therapy.
authors.affiliation: Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, People's Republic of China.|Institute of Brain Science, Harbin Medical University, Harbin, Heilongjiang, 150001, People's Republic of China.
authors.forename: Yunke
authors.initials: Y
authors.lastname: Bi
authors.affiliation: Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, People's Republic of China.|Institute of Brain Science, Harbin Medical University, Harbin, Heilongjiang, 150001, People's Republic of China.
authors.forename: Chen
authors.initials: C
authors.lastname: Shen
authors.affiliation: Department of Neurosurgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, People's Republic of China.
authors.forename: Chenguang
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, People's Republic of China.|Institute of Brain Science, Harbin Medical University, Harbin, Heilongjiang, 150001, People's Republic of China.
authors.forename: Yaohua
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Endocrinology, General Hospital of HeiLongJiang Agricultural Reclamation Department, Harbin, Heilongjiang, 150001, People's Republic of China.
authors.forename: Dandan
authors.initials: D
authors.lastname: Gao
authors.affiliation: Department of Neurological Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Shi
authors.affiliation: Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, People's Republic of China.|Institute of Brain Science, Harbin Medical University, Harbin, Heilongjiang, 150001, People's Republic of China.
authors.forename: Fei
authors.initials: F
authors.lastname: Peng
authors.affiliation: Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, People's Republic of China.|Institute of Brain Science, Harbin Medical University, Harbin, Heilongjiang, 150001, People's Republic of China.
authors.forename: Zhendong
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, People's Republic of China.|Institute of Brain Science, Harbin Medical University, Harbin, Heilongjiang, 150001, People's Republic of China.
authors.forename: Boxian
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, People's Republic of China.|Institute of Brain Science, Harbin Medical University, Harbin, Heilongjiang, 150001, People's Republic of China.
authors.forename: Zhixing
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, People's Republic of China.|Institute of Brain Science, Harbin Medical University, Harbin, Heilongjiang, 150001, People's Republic of China.
authors.forename: Xiaoxiong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, People's Republic of China.|Institute of Brain Science, Harbin Medical University, Harbin, Heilongjiang, 150001, People's Republic of China.
authors.forename: Xu
authors.initials: X
authors.lastname: Hou
authors.affiliation: Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, People's Republic of China.|Institute of Brain Science, Harbin Medical University, Harbin, Heilongjiang, 150001, People's Republic of China.
authors.forename: Huailei
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, People's Republic of China.|Institute of Brain Science, Harbin Medical University, Harbin, Heilongjiang, 150001, People's Republic of China.
authors.forename: Jianing
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Pain Medicine, Third Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, People's Republic of China.
authors.forename: Huichao
authors.initials: H
authors.lastname: Zou
authors.affiliation: Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, People's Republic of China.|Institute of Brain Science, Harbin Medical University, Harbin, Heilongjiang, 150001, People's Republic of China.
authors.forename: Kaikai
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, People's Republic of China.|Institute of Brain Science, Harbin Medical University, Harbin, Heilongjiang, 150001, People's Republic of China.
authors.forename: Chen
authors.initials: C
authors.lastname: Zhong
authors.affiliation: Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, People's Republic of China.|Institute of Brain Science, Harbin Medical University, Harbin, Heilongjiang, 150001, People's Republic of China.
authors.forename: Jiakang
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Section of Neurosurgery, Department of Surgery, The University of Chicago Medical Center and Pritzker School of Medicine, Chicago, IL, USA.
authors.forename: Changbin
authors.initials: C
authors.lastname: Shi
authors.affiliation: Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, People's Republic of China. guangsz@hotmail.com.|Institute of Brain Science, Harbin Medical University, Harbin, Heilongjiang, 150001, People's Republic of China. guangsz@hotmail.com.
authors.forename: Shiguang
authors.initials: S
authors.lastname: Zhao
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology; D005910:Glioma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D006801:Humans; D008297:Male; D009367:Neoplasm Staging; D011794:Quercetin / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C025946:3-methyladenine; D002738:Chloroquine; D011794:Quercetin; D000225:Adenine
keywords: Apoptosis; Autophagy; Glioma; Quercetin