Department of Pharmaceutical Sciences, Cedarville University School of Pharmacy, Cedarville University, Cedarville, Ohio, USA.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
Cancer Rep (Hoboken). 2024 May;7(5):e2051. doi: 10.1002/cnr2.2051.
Glioblastomas are characterized by aggressive behavior. Surgery, radiotherapy, and alkylating agents, including temozolomide are the most common treatment options for glioblastoma. Often, conventional therapies fail to treat these tumors since they develop drug resistance. There is a need for newer agents to combat this deadly tumor. Natural products such as gedunin have shown efficacy in several human diseases. A comprehensive study of gedunin, an heat shock protein (HSP)90 inhibitor, has not been thoroughly investigated in glioblastoma cell lines with different genetic modifications.
A key objective of this study was to determine how gedunin affects the biological and signaling mechanisms in glioblastoma cells, and to determine how those mechanisms affect the proliferation and apoptosis of glioblastoma cells.
The viability potentials of gedunin were tested using MTT, cell counts, and wound healing assays. Gedunin's effects on glioma cells were further validated using LDH and colony formation assays. In addition, we investigated the survival and apoptotic molecular signaling targets perturbed by gedunin using Western blot analysis and flow cytometry.
Our results show that there was a reduction in cell viability and inhibition of wound healing in the cells tested. Western blot analysis of the gene expression data revealed genes such as EGFR and mTOR/Akt/NF kappa B to be associated with gedunin sensitivity. Gedunin treatment induced apoptosis by cleaving poly ADP-ribose polymerase, activating caspases, and downregulating BCL-xL. Based on these results, gedunin suppressed cell growth and HSP client proteins, resulting in apoptosis in glioblastoma cell lines.
Our data provide in vitro support for the anticancer activity of gedunin in glioma cells by downregulating cancer survival proteins.
神经胶质瘤的特征是具有侵袭性。手术、放疗和烷化剂（包括替莫唑胺）是神经胶质瘤最常见的治疗选择。然而，由于这些肿瘤会产生药物耐药性，常规疗法往往无法治疗它们。因此，需要新的药物来对抗这种致命的肿瘤。天然产物如 gedunin 在多种人类疾病中表现出疗效。然而，对于具有不同遗传修饰的神经胶质瘤细胞系，尚未对 gedunin（一种热休克蛋白 (HSP)90 抑制剂）进行全面研究。
本研究的一个主要目标是确定 gedunin 如何影响神经胶质瘤细胞的生物学和信号机制，并确定这些机制如何影响神经胶质瘤细胞的增殖和凋亡。
使用 MTT、细胞计数和划痕愈合实验测试了 gedunin 的生存能力。使用 LDH 和集落形成实验进一步验证了 gedunin 对神经胶质瘤细胞的影响。此外，我们还通过 Western blot 分析和流式细胞术研究了 gedunin 扰乱的生存和凋亡分子信号靶标。
我们的结果表明，在测试的细胞中，细胞活力降低，伤口愈合受到抑制。基因表达数据的 Western blot 分析显示，EGFR 和 mTOR/Akt/NF kappa B 等基因与 gedunin 敏感性相关。Gedunin 处理通过切割多聚 ADP-核糖聚合酶、激活半胱天冬酶和下调 BCL-xL 诱导细胞凋亡。基于这些结果，gedunin 抑制了 HSP 客户蛋白的表达，从而抑制了神经胶质瘤细胞系的细胞生长和凋亡。
我们的数据通过下调癌症存活蛋白，为 gedunin 在神经胶质瘤细胞中的抗癌活性提供了体外支持。
