许多植物衍生的化合物通过增强肿瘤细胞的凋亡相关途径和细胞周期损伤被证明是有前途的抗肿瘤治疗剂。包括胶质母细胞瘤(GBM)细胞系。我们旨在回顾四种在GBM细胞系中有效的天然植物化合物作为咖啡因,甘草酸二钾(DPG),姜黄素,还有euphol.此外,研究了这些植物化合物通过microRNAs(miRs)调节对GBM细胞系的抗肿瘤作用。然而,只有DPG和姜黄素被发现对miR调节有效。咖啡因通过抑制细胞周期蛋白依赖性激酶(CDK)复合物并通过降低BCL-2和增加FOXO1表达水平而将GBM细胞周期阻滞在G0/G1期,从而导致更大的凋亡活性。咖啡因还能直接抑制IP3R3、p38磷酸化,和rho相关蛋白激酶(ROCK),通过抑制组织抑制剂金属蛋白酶-1(TIMP-1)和整合素β1和β3来降低细胞侵袭和迁移能力,或间接降低基质金属蛋白酶,MMP-2和MMP-9。DPG在GBM细胞中表现出与IRAK2和TRAF6介导的miR-16和miR-146a抑制核因子κB(NF-κB)途径相关的抗肿瘤作用,分别。最近,观察到DPG上调miR-4443和miR-3620,负责通过CD209和TNC调节转录后抑制NF-κB途径,分别导致较低的MMP-9和迁移能力。姜黄素能够增加miR-223-3p,miR-133a-3p,miR-181a-5p,miR-34a-5p,miR-30c-5p,和miR-1290表达导致丝氨酸或苏氨酸激酶(AKT)途径受损,并且还降低miR-27a-5p,miR-221-3p,miR-21-5p,miR-125b-5p,和miR-151-3p表达导致p53-BCL2通路抑制,细胞凋亡。有趣的是,通过姜黄素作用降低miR-27a的表达增强了C/EBP同源蛋白(CHOP)的表达,导致俯卧。姜黄素可以抑制miR-21的表达,从而通过caspase3和死亡受体(DR)4和5的激活激活细胞凋亡。自噬受与Atg家族相互作用的LC-3蛋白控制,以形成LC3-II并激活自噬。Euphol可以直接增强GBM细胞中的LC3-II水平或通过PDK1调节抑制肿瘤侵袭和迁移。
Many plant-derived compounds are shown to be promising antitumor therapeutic agents by enhancing apoptosis-related pathways and cell cycle impairment in tumor cells, including glioblastoma (GBM) cell lines. We aimed to review four natural plant compounds effective in GBM cell lines as caffeine, dipotassium glycyrrhizinate (DPG), curcumin, and
euphol. Furthermore, antitumoral effect of these plant compounds on GBM cell lines through microRNAs (miRs) modulation was investigated. However, only DPG and curcumin were found as effective on miR modulation. Caffeine arrests GBM cell cycle in G0/G1 phase by cyclin-dependent kinases (CDK) complex inhibition and by decreasing BCL-2 and increasing FOXO1 expression levels causing greater apoptotic activity. Caffeine can also directly inhibit IP3R3, p38 phosphorylation, and rho-associated protein kinase (ROCK), decreasing cell invasion and migration capacity or indirectly by inhibiting the tissue inhibitor metalloproteinase-1 (TIMP-1) and integrins β1 and β3, leading to lower matrix metalloproteinases, MMP-2 and MMP-9. DPG presents antitumoral effect in GBM cells related to nuclear factor kappa B (NF-κB) pathway suppression by IRAK2 and TRAF6-mediating miR-16 and miR-146a, respectively. More recently, it was observed that DPG upregulated miR-4443 and miR-3620, responsible for post-transcriptional inhibition of the NF-κB pathway by CD209 and TNC modulation, respectively leading to lower MMP-9 and migration capacity. Curcumin is able to increase miR-223-3p, miR-133a-3p, miR-181a-5p, miR-34a-5p, miR-30c-5p, and miR-1290 expression leading to serine or threonine kinase (AKT) pathway impairment and also it decreases miR-27a-5p, miR-221-3p, miR-21-5p, miR-125b-5p, and miR-151-3p expression causing p53-BCL2 pathway inhibition and consequently, cellular apoptosis. Interestingly, lower expression of miR-27a by curcumin action enhanced the C/EBP homologous protein(CHOP) expression, leading to paraptosis. Curcumin can inhibit miR-21 expression and consequently activate apoptosis through caspase 3 and death receptor (DR) 4 and 5 activation. Autophagy is controlled by the LC-3 protein that interacts with Atg family for the LC3-II formation and autophagy activation.
Euphol can enhance LC3-II levels directly in GBM cells or inhibits tumor invasion and migration through PDK1 modulation.