title: Metformin and temozolomide act synergistically to inhibit growth of glioma cells and glioma stem cells in vitro and in vivo.
abstract: Glioblastoma (GBM) is the most frequent and aggressive brain tumor in adults. In spite of advances in diagnosis and therapy, the prognosis of patients with GBM has remained dismal. The fast recurrence and multi-drug resistance are some of the key challenges in combating brain tumors. Glioma stem cells (GSCs) which are considered the source of relapse and chemoresistance, the need for more effective therapeutic options is overwhelming. In our present work, we found that combined treatment with temozolomide (TMZ) and metformin (MET) synergistically inhibited proliferation and induced apoptosis in both glioma cells and GSCs. Combination of TMZ and MET significantly reduced the secondary gliosphere formation and expansion of GSCs. We first demonstrated that MET effectively inhibited the AKT activation induced by TMZ, and a combination of both drugs led to enhanced reduction of mTOR, 4EBP1 and S6K phosphorylation. In addition, the combination of the two drugs was accompanied with a powerful AMP-activated protein kinase (AMPK) activation, while this pathway is not determinant. Xenografts performed in nude mice demonstrate in vivo demonstrated that combined treatment significantly reduced tumor growth rates and prolonged median survival of tumor-bearing mice. In conclusion, TMZ in combination with MET synergistically inhibits the GSCs proliferation through downregulation of AKT-mTOR signaling pathway. The combined treatment of two drugs inhibits GSCs self-renewal capability and partly eliminates GSCs in vitro and in vivo. This combined treatment could be a promising option for patients with advanced GBM.
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, Changchun, China.
authors.forename: Zhiyun
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, Changchun, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Zhao
authors.affiliation: Department of Obstetrics and Gynecology, First Hospital of Jilin University, Changchun, China.
authors.forename: Guifang
authors.initials: G
authors.lastname: Xie
authors.affiliation: Department of Clinical Laboratory, Second Hospital of Jilin University, Changchun, China.
authors.forename: Liyan
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, Changchun, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, Changchun, China.
authors.forename: Hongquan
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, Changchun, China.
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Experimental Pharmacology and Toxicology, School of Pharmacy, Jilin University, Changchun, China.
authors.forename: Cai
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, Changchun, China.
authors.forename: Yunqian
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects; D011897:Random Allocation; D015398:Signal Transduction; D000077204:Temozolomide; D023041:Xenograft Model Antitumor Assays
chemical_list: D003606:Dacarbazine; D008687:Metformin; D000077204:Temozolomide
keywords: AKT-mTOR; AMPK; glioma stem cell; metformin; temozolomide