RT Journal Article
SR Electronic
T1 <strong>Exploring mGluR3 NAM as a new drug for improving treatment of Glioblastoma</strong><strong/>
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 1232
OP 1232
VO 61
IS supplement 1
A1 Qu, Xiying
A1 Wang, Junfeng
A1 Afshar, Sepideh
A1 Takahashi, Kazue
A1 Choi, Hak Soo
A1 El Fakhri, Georges
A1 Zhang, Zhaoda
A1 Brownell, Anna-Liisa
YR 2020
UL http://jnm.snmjournals.org/content/61/supplement_1/1232.abstract
AB 1232Objectives: Glioblastoma (GBM) is the most common malignant primary brain tumor. The current standard therapies including surgery, radiotherapy and chemotherapies improve patient’s survival, however, GBM remains among the most lethal and resistant human tumor because of the poor prognosis. Thus, there is an urgent medical need for developing new drugs that specifically regulate GBM proliferation or differentiation to improve the treatment of GBM. The excessive secretion of glutamate by glioma cells plays an important role in tumor malignancy. Emerging evidences have suggested the roles of mGluRs in GBM pathology, in which mGluR3 was found in cells isolated from surgically removed GBM, in glioma cell lines and in glioma stem cells (GSC). The negative correlation between mGluR3 expression in malignant gliomas and therapeutic response to chemotherapy strongly encourages the development of mGluR3 negative allosteric modulators (NAMs) as novel anti-cancer agents that might reduce proliferation and enhance differentiation of tumor cells and restrain some mechanisms of chemo-resistance. Methods: We have synthesized a mGluR3 NAM, mG3N001, and evaluated it in U-118 MG glioma cell line. MTT assay was used to detect if mG3N001 could affect the proliferation of U-118 MG cells, Hoechst 33342 staining was used to evaluate if mG3N001 could induce apoptosis, flow cytometry was used to investigate if mG3N001 could change the phase of U-118 MG cell cycles, and western blotting was used to reveal that the pathway maybe involve. Results: The results showed that the mGluR3 blockade by mG3N001 significantly decreased mGluR3 expression and reduced the proliferation of U-118 MG cells by arresting cells in the stationary phase of G1, preventing the cell cycle into S phase and G2 phase and limiting DNA replication and mitosis. It was also found that mGluR3 inhibition markedly decreased activation of PI3K pathways and inhibited P-AKT and P-mTOR phosphorylation. Conclusions: All together, these findings suggest that mGluR3 NAM could be a potential drug to improve treatment of Glioblastoma. Acknowledgements: The authors would like to acknowledge supporting research grants R01EB021708 and R01EB012864.