title: Temozolomide in combination with metformin act synergistically to inhibit proliferation and expansion of glioma stem-like cells.
abstract: Glioblastoma is the most common and most aggressive brain tumor in adults. The introduction of temozolomide (TMZ) has advanced chemotherapy for malignant gliomas, but it is not curative. The difficulties in treating glioblastoma may be as a result of the presence of glioma stem cells (GSCs), which are a source of relapse and chemoresistance. Another reason may be that endogenous Akt kinase activity may be activated in response to clinically relevant concentrations of TMZ. Akt activation is correlated with the increased tumorigenicity, invasiveness and stemness of cancer cells and overexpression of an active form of Akt increases glioma cell resistance to TMZ. Mounting evidence has demonstrated that cancer stem cells are preferentially sensitive to an inhibitor of Akt and down-regulation of the PI3K/Akt pathway may enhance the cytotoxicity of TMZ. Metformin (MET), the first-line drug for treating diabetes, it has been proved that it reduces AKT activation and selectively kills cancer stem cells, but whether it can potentiate the cytotoxicity of TMZ for GSCs remains unknown. In the present study, the GSCs isolated from human glioma cell line U87 and Rat glioma cell line C6,in vitrotreatment with TMZ either alone or with MET. The present study demonstrates that MET acts synergistically with TMZ in inhibiting GSCs proliferation and generating the highest apoptotic rates when compared to either drug alone. These findings implicate that GSCs cytotoxicity mediated by TMZ may be stimulated by MET, have a synergistic effect, but the definite mechanisms remain elusive.
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China.
authors.forename: Zhiyun
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China.
authors.forename: Gang
authors.initials: G
authors.lastname: Zhao
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China.
authors.forename: Pengliang
authors.initials: P
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China.
authors.forename: Yunqian
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China.
authors.forename: Guangtong
authors.initials: G
authors.lastname: Zhou
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Obstetrics and Gynecology, First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China.
authors.forename: Guifang
authors.initials: G
authors.lastname: Xie
keywords: Akt; cancer stem cell; glioma; metformin; temozolomide