Original ContributionResveratrol enhances the therapeutic effect of temozolomide against malignant glioma in vitro and in vivo by inhibiting autophagy
Graphical abstract
Highlights
► Temozolomide (TMZ) induces both apoptosis and autophagy in the glioma cells. ► ROS/ERK-mediated autophagy induced by TMZ plays a pro-survival role. ► Resveratrol enhances TMZ-induced apoptosis by inhibiting ROS and autophagy. ► Resveratrol exhibits a synergistic effect on TMZ-mediated cytotoxicity. ► Co-administration of resveratrol and TMZ reduces tumor volumes in vivo.
Section snippets
Reagents and antibodies
Media such as RPMI 1640, MEM, and DMEM were purchased from Hyclone (Logan, UT, USA). Vitamin C and 3-(4,5-dimethyl-2-thiazolyl)-2,5-dimethyl-2H-tetrazolium bromide (MTT) were purchased from Merck (Darmstadt, Germany). TMZ, resveratrol, acridine orange, 3-methyladenine (3-MA), bafilomycin A1 (BAF), chloroquine (CQ), ammonium chloride (AC), and tiron were purchased from Sigma (St. Louis, MO, USA). 2,7-Dihydrodichlorofluorescein diacetate (DCFH-DA), dihydroethidium (HEt), and dihydrorhodamine 123
TMZ induces apoptosis in glioma cells
To examine the cytotoxicity of TMZ in various glioma cells, the U87 MG (obtained from a Caucasian strain), GBM8401, and GBM cell lines (both from Asian strains) were subjected to MTT assay to determine cell viability. Referring to the concentrations (0–1000 μM) used in the study of Aoki et al. [24], the cells were treated with 0–500 μM TMZ for 72 h. As shown in Fig. 1A, TMZ inhibited cell growth in a dose-dependent manner in three glioma cell lines. The IC50 of TMZ was calculated as 397.2, 391.4,
Discussion
Recent studies have demonstrated the median overall survival rate for glioblastoma patients to be 10.2–14.6 months [29]. However, progress remains poor, even with treatment that combines surgery, radiation, and/or chemotherapy [30]. Although TMZ is a major chemotherapeutic agent used clinically to mediate GBM cell death, the increase in median survival time of 2 months is modest [31]. In this study, we demonstrated both in vitro and in vivo that resveratrol, a natural polyphenol, potentiated the
Acknowledgments
This study was sponsored by grants from the National Science Council (NSC99-2320-B-038-008-MY3) and Shin Kong Wu Ho-Su Memorial Hospital, Taiwan (SKH-TMU-96-11) to C.M.S.
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