Shabierjiang Jiapaer, Takuya Furuta, Yu Dong, Tomohiro Kitabayashi, Hemragul Sabit, Jiakang Zhang, Guangtao Zhang, Shingo Tanaka, Masahiko Kobayashi, Atsushi Hirao and Mitsutoshi Nakada* Pages 4675 - 4684 ( 10 )
Background: Glioblastomas (GBMs) are aggressive malignant brain tumors. Although chemotherapy with temozolomide (TMZ) can extend patient survival, most patients eventually demonstrate resistance. Therefore, novel therapeutic agents that overcome TMZ chemoresistance are required to improve patient outcomes.
Purpose: Drug screening is an efficient method to find new therapeutic agents from existing drugs. In this study, we explored a novel anti-glioma agent by drug screening and analyzed its function with respect to GBM treatment for future clinical applications.
Methods: Drug libraries containing 1,301 diverse chemical compounds were screened against two glioma stem cell (GSC) lines for drug candidate selection. The effect of selected agents on GSCs and glioma was estimated through viability, proliferation, sphere formation, and invasion assays. Combination therapy was performed to assess its ability to enhance TMZ cytotoxicity against GBM. To clarify the mechanism of action, we performed methylation-specific polymerase chain reaction, gelatin zymography, and western blot analysis.
Results: The acyl-CoA synthetase inhibitor 2-fluoropalmitic acid (2-FPA) was selected as a candidate anti-glioma agent. 2-FPA suppressed the viability and stem-like phenotype of GSCs. It also inhibited proliferation and invasion of glioma cell lines. Combination therapy of 2-FPA with TMZ synergistically enhanced the efficacy of TMZ. 2-FPA suppressed the expression of phosphor-ERK, CD133, and SOX-2; reduced MMP-2 activity; and increased methylation of the MGMT promoter.
Conclusion: 2-FPA was identified as a potential therapeutic agent against GBM. To extend these findings, physiological studies are required to examine the efficacy of 2-FPA against GBM in vivo.
Glioma, drug screening, 2-fluoropalmitic acid, temozolomide, matrix metalloproteinase, glioma stem cells.
Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Department of Pathology, Kurume University, Kurume, Shenzhen SAMII Medical Center, Shenzhen, Guangdong Province, Department of Neurosurgery, Fukui Prefectural Hospital, Fukui, Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Division of Molecular Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Division of Molecular Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa