Abstract 4221: Inhibition of glioblastoma tumorsphere by combination of 2-deoxyglucose and metformin
Authors: Eui Hyun Kim, Ji-Hyun Lee, Yoonjee Oh, Jin-Kyoung Shim, Jun Jeong Choi, Jong Hee Chang, Sun Ho Kim, Jae-Ho Choeng, Pilnam Kim, Seok-Gu Kang
Journal: Cancer Research (2015)

Abstract The treatment failure of glioblastoma (GBM) is thought to be the presence of refractory cancer cells. It has been suggested that deprivation of tumor bioenergetics by inhibition of multiple energy pathways could be an effective new therapeutic approach for various human tumors. However, the effectiveness of this idea has not been evaluated in GBM tumorspher (TS) model. We hypothesized that the dual inhibition of glycolysis and oxidative phosphorylation could suppress GBM TS effectively. We evaluate the effect of 2-deoxyglucose (2-DG), metformin alone, and their combination in the comparison of temozolomide. The viability of GBM TS was tested in different conditions, and protein expression related to adenosine monophosphate-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) pathway were examined. The influence of combination treatment on cytotoxicity, stemness and invasion properties of GBM TSs were evaluated with sphere formation assay and 3-demensional culture system. Glucose metabolism was checked with 18fluorodeoxyglucose (18FDG) positron emission tomography (PET) scan. Microarray was performed and its results were analyzed with gene set enrichment analysis. Lastly, animal experiment was performed with mouse orthotopic xenograft model in different conditions. Viability of GBM TS were not decreased by any single or combination treatments of 2-DG and metformin. However, mTOR-related proteins were down-regulated with AMPK-independent manner. Sphere was not formed with 2DG, metformin combination treatment and the proteins related to stemness were less expressed as well. Invasion capacity of GBM TS was dramatically inhibited by combination treatment in the 3D invasion model assay. PET scan showed the radioactivity of 18FDG uptake was decreased in the TS which was treated by combination drugs. Transcriptome assay with gene set enrichment analysis showed several genes related to extracellular matrix and adhesion, cellular metabolism were turned off or turned on after combination treatment. Combination of 2-DG and metformin showed survival benefit, and the examination of their autopsied brain revealed decreased invasion of GBM TS. The combination of 2-DG and metformin did not show cytotoxicity for GBM TS. But, dual inhibition (2DG and metformin) effectively decreased the stemness and invasion capacity of GBM TS, and showed potential survival benefit in mouse orthotopic xenograft model experiment. We believe this dural inhibition (2DG and metformin) would be helpful in the treatment of GBM patients by targeting GBM TS. Citation Format: Eui Hyun Kim, Ji-Hyun Lee, Yoonjee Oh, Jin-Kyoung Shim, Jun Jeong Choi, Jong Hee Chang, Sun Ho Kim, Jae-Ho Choeng, Pilnam Kim, Seok-Gu Kang. Inhibition of glioblastoma tumorsphere by combination of 2-deoxyglucose and metformin. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4221. doi:10.1158/1538-7445.AM2015-4221