Glioblastoma belongs to grade IV tumors and is one of the most common aggressive brain cancers. Current treatment for GBM is the combination of surgical resection with radiation therapy and chemotherapy using temozolomide (TMZ). However, these treatments still bring poor outcomes due to complex pathogenesis like gene mutation and cellular pathway alteration. Thus, identifying novel potent drugs with less adverse effects on the normal cells with a broad spectrum is significantly necessary to combat the severity of the GBM disease progression.
Phenolic compounds are promising structural units that have been identified to possess valuable properties such as anti-viral, anti-tumor, anti-bacterial, and anti-inflammatory in developing therapeutic compounds. The FDA has approved several compounds derived from phenols, thus indicating the potential of phenolic compounds in treating cancer. In addition, several preclinical studies have shown the efficacy of G protein-coupled receptors (GPCRs) based therapies in GBM treatment. Among the vast majority of orphan GPCRs, GPR17 is identified as a possible candidate for treating many neuronal diseases including GBM.
Phuong Doan’s study aims to identify a novel strategy to combat GBM. Phuong performed an extensive investigation of three phenolic compounds and GPR17 ligands for their potential activities against GBM.
She carried out kinetic and dynamic cytotoxicity, migration, invasion, colony, cell cycle arrest, apoptosis, calcium, cellular oxidative potential (ROS), and caspase activity assays. In her study, whole genome sequencing was performed to identify the modulated genes and the corresponding signaling pathways that have been affected by the treatment.
Her study reveals that THTMP as the best compound possessing the highest inhibitory effect among three phenolic compounds. THTMP was found to have the ability to target gliomas cancer stem cells by modulating EGFR and cancer stem cell signaling pathways. In addition, T0, a GPR17 ligand, successfully binds to GPR17 receptor and activates corresponding downstream signaling, thus decreases cAMP level.
The study reports that T0 could inhibit GBM cell growth through ROS-mediated apoptosis. T0 was found to regulate numerous signaling pathways such as PI3K-Akt, STAT, NF-kB and MAPK.
Given the benefits of combination therapy development, she characterized the synergistic effect of THTMP and T0 for treating GBM. Her study shows that THTMP has a higher effect in combination with T0 than the known chemotherapeutic agent, TMZ. The potential activity of this combination in inducing cell death is strongly associated with ROS-, caspase- and mitogen‑activated protein kinase (MAPK)-mediated apoptosis.
Furthermore, the combinatorial drug treatment shows the promising anti-tumor property in the GBM xenograft model by reducing the tumor volume, suggesting it as an alternative drug to TMZ. Therefore, this combination of phenolic compound (THTMP) and GPR17 ligand (T0) could be used as a novel therapy to combat GBM.
The study was carried out in the Molecular Signaling Group, under the supervision of Docent Meenakshisundaram Kandhavelu, University lecturer and Professor Olli Yli-Harja, Computational Systems Biology Group.
The doctoral dissertation of M.Sc. (Tech) Phuong Doan, in the field of Biomedical Sciences and Engineering, entitled Novel Treatment Strategies for Glioblastoma Therapeutic Potential of Phenolic Derivatives and Orphan G-protein Coupled Receptor Ligand will be publicly examined in the Faculty of Medicine and Health Technology of Tampere University at 12.00 pm EEST, Friday 18th March 2022. The Opponent will be Professor Stefania Maria Ceruti from the Department of Pharmacology and Biomolecular Sciences, University of Milan, Italy. The Custos will be Professor Olli Yli-Harja, from the Faculty of Medicine and Health Technology, Tampere University.
The event can be followed via remote connection.
The dissertation is available online at
https://urn.fi/URN:ISBN:978-952-03-2308-0
The Faculty Office will provide a pdf version of the entire doctoral dissertation upon request. Please send an email to met.doc.tau [at] tuni.fi
Photo: Cao Thanh Nguyen