Abstract
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.
Highlights
The central nervous system (CNS) tumors account for about 3% of all neoplasms [1]
According to the World Health Organization (WHO), astrocytomas are divided into four degrees of malignancy, which are based on histopathological criteria such as the presence of atypical cells, mitosis, endothelial proliferation, and necrosis; and molecular depending on the presence or absence of mutations in the isocitrate dehydrogenase 1 and 2 genes (IDH1 and IDH2) [4]
It was reported that caffeine consumption might be associated with lower glioma risk [36]
Summary
Glial tumors or gliomas comprise 50% of all CNS tumors and 80% of all brain-initiating malignant tumors [2]. Gliomas are subdivided into astrocytomas, oligodendrogliomas, and ependymomas [3]. Malignant gliomas are the most common primary brain tumor, representing 42% of CNS tumors [5]. The most common aggressive glioma form is known as glioblastoma (GBM) or WHO grade IV has a 12–15-month medium survival rate. The lower-grade gliomas (WHO grades II and III) appear less aggressive at the time of diagnosis but eventually progress into a malignant phase within 5–10 years [6]. Despite the surgical procedures and treatment regimens with radiation and chemotherapy, malignant gliomas remain incurable [6], due to their resistance to all conventional therapies and the diffuse infiltrative nature of the tumor cells
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