Abstract
Glioblastoma (GBM) is the most common type of malignant brain tumor in adults. We show here that small molecule 2-[(3,4-dihydroquinolin-1(2H)-yl)(p-tolyl)methyl]phenol (THTMP), a potential anticancer agent, increases the human glioblastoma cell death. Its mechanism of action and the interaction of selective signaling pathways remain elusive. Three structurally related phenolic compounds were tested in multiple glioma cell lines in which the potential activity of the compound, THTMP, was further validated and characterized. Upon prolonged exposer to THTMP, all glioma cell lines undergo p53 and cyclin-dependent kinase mediated cell death with the IC50 concentration of 26.5 and 75.4 μM in LN229 and Snb19, respectively. We found that THTMP strongly inhibited cell growth in a dose and in time dependent manner. THTMP treatment led to G1/S cell cycle arrest and apoptosis induction of glioma cell lines. Furthermore, we identified 3,714 genes with significant changes at the transcriptional level in response to THTMP. Further, a transcriptional analysis (RNA-seq) revealed that THTMP targeted the p53 signaling pathway specific genes causing DNA damage and cell cycle arrest at G1/S phase explained by the decrease of cyclin-dependent kinase 1, cyclin A2, cyclin E1 and E2 in glioma cells. Consistently, THTMP induced the apoptosis by regulating the expression of Bcl-2 family genes and reactive oxygen species while it also changed the expression of several anti-apoptotic genes. These observations suggest that THTMP exerts proliferation activity inhibition and pro-apoptosis effects in glioma through affecting cell cycle arrest and intrinsic apoptosis signaling. Importantly, THTMP has more potential at inhibiting GBM cell proliferation compared to TMZ, the current chemotherapy treatment administered to GBM patients; thus, we propose that THTMP may be an alternative therapeutic option for glioblastoma.
Highlights
Glioblastoma (GBM) is known as the most aggressive primary brain tumor
After determining the gene expression profile, we focused on the cell cycle arrest and the apoptosis pathway activated by our alkylaminophenol and investigated the significant of cell cycle genes as well as proapoptosis and anti-apoptosis genes in gliomas chemotherapeutic resistance
Our results show that genes involves in DNA damage, DNA replication, cell cycle arrest and apoptosis induction were transcriptionally modulated and highly enriched when GBM cells were treated with THTMP
Summary
Glioblastoma (GBM) is known as the most aggressive primary brain tumor. different treatments have been combined such as surgical operation, chemotherapy, or radiotherapy, no standard treatment has been proven to be effective for treating brain tumor. In the past few decades, many efforts have been made in understanding chemotherapy-induced DNA damage response (DDR) such as activation of checkpoint, repair and cell death pathways. Several key regulatory elements of cell cycle and apoptosis alter the expression of cyclin-dependent kinases such as Bcl-2 protein family, p53 protein, inhibitor of apoptosis proteins (IAPs) or receptor tyrosine kinases like the epidermal growth factor receptor (EGFR) and their down-stream signaling cascade. Among these signaling pathways, p53 plays an essential role in cellular responses to DNA damage and regulation of cell cycle and apoptosis. P53 may promote apoptosis through transcription-independent mechanisms and direct interactions with members of the Bcl-2 family of proteins in the cytosol or mitochondria
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
