Identification of 2-Fluoropalmitic Acid as a Potential Therapeutic Agent Against Glioblastoma
Identification of 2-Fluoropalmitic Acid as a Potential Therapeutic Agent Against Glioblastoma
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DOI：
10.2174/1381612826666200429092742
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发表时间：
2020-01-01
影响因子：
3.1
通讯作者：
Nakada, Mitsutoshi
中科院分区：
文献类型：
--
作者：
Jiapaer, Shabierjiang;Furuta, Takuya;Nakada, Mitsutoshi
背景：胶质母细胞瘤（GBM）是侵袭性恶性脑肿瘤。虽然替莫唑胺（TMZ）化疗可以延长患者的生存期，但大多数患者最终表现出耐药性。因此，需要克服TMZ耐药性的新型治疗药物来改善患者的治疗效果。目的：药物筛选是从现有药物中寻找新治疗药物的有效方法。在这项研究中，我们探索了一种新的抗胶质瘤药物的药物筛选和分析其功能方面的GBM治疗为未来的临床应用程序。方法：药物库包含1,301个不同的化合物筛选对两个胶质瘤干细胞（GSC）株的候选药物选择。通过活力、增殖、球体形成和侵袭测定来评估所选药剂对GSC和胶质瘤的作用。进行组合疗法以评估其增强TMZ对GBM的细胞毒性的能力。为了阐明其作用机制，我们进行了甲基化特异性聚合酶链反应，明胶酶谱，和western blot analysis.Results：酰基辅酶A合成酶抑制剂2-氟棕榈酸（2-FPA）被选为候选抗胶质瘤剂。2-FPA抑制GSC的活力和干细胞样表型。对胶质瘤细胞的增殖和侵袭也有抑制作用。2-FPA与TMZ联合治疗可协同增强TMZ的疗效。2-FPA抑制磷酸化ERK、CD13.3和SOX-2的表达，降低MMP-2活性，并增加MGMT启动子的甲基化。结论：2-FPA被鉴定为一种潜在的抗GBM治疗剂。为了扩展这些发现，需要进行生理学研究以检查2-FPA在体内对GBM的功效。
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, CD13.3, 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.