<p>Toosendanin Suppresses Glioma Progression Property and Induces Apoptosis by Regulating miR-608/Notch Axis</p>

Abstract

Background: Glioma is one the most common and aggressive primary tumors of adult central nervous system worldwide, which tends to develop dysplasia and metastasis. Recently, toosendanin (TSN) has shown pharmacological effects in several cancers. However, little is known about the underlying mechanism of the effect of TSN on glioma and its relationship between miRNA in glioma. Methods: Cell proliferation, cell cycle, cell apoptosis and cell migration were analyzed by CCK-8 cell viability, flow cytometry, wound scratch healing, transwell and Western blotting assays, respectively, in vitro. The regulation relationships between TSN and miR-608 or between miR-608 and Notch1 (Notch2) were examined using qRT-PCR, dual-luciferase and Western blotting assays. The functional effects of TSN through regulating miR-608 and Notch1 (Notch2) were further examined using a xenograft tumor mouse model in vivo. Results: After TSN concentration was increased from 50 nM, 100 nM to 150 nM, cell proliferation and cell cycle were gradually reduced, and the cell apoptosis rate was increased in U-138MG or U-251MG cells. Wound-healing and transwell assays results showed that cell migration was significantly inhibited in TSN treatment cells (TSN treatment, 50 nM) compared to control cells. Mechanistic studies revealed that TSN up-regulated the expression of microRNA-608 (miR-608), while down-regulated the expression of miR-608's target, Notch1 and Notch2. Over-expression of Notch1 and Notch2 partly attenuated TSN-induced tumor suppressive function. Moreover, in vivo experiments revealed that TSN treatment led to a significant inhibition of tumor growth, suggesting that it might be a promising drug for the treatment of glioma. Conclusion: In the present study, a novel established functional manner of TSN/miR-608/ Notch1 (Notch2) axis was systematically indicated, which might provide prospective intervention ways for glioma therapy.

Mechanisms involved in the anti-tumor effects of Toosendanin in glioma cells

“…Apoptosis is known as a form of programmed cell death, and its inhibition leads to unlimited growth of tumor cells [30]. Previous studies have shown that TSN can induce tumor cell apoptosis [15,23]. These results were consistent with our finding that TSN-induced apoptosis is achieved through the activation of a cascade of reactions including the caspase cascade and increased ratio of Bax/Bcl-2.…”

“…Studies have recently shown the anti-tumor effects of TSN on different types of malignant tumors [21]; however, the role of TSN in glioma remains unclear. Studies regarding the anti-glioma role of TSN are limited; however, few have shown that the mechanism involves the p53 and mir-608/notch axis [22,23]. For the first time, we propose the role of TSN in the inhibition of the viability and metastasis of glioma cells through the promotion of induced apoptosis and inhibition of the PI3K/Akt/mTOR pathway.…”

Mechanisms Involved in the Anti-Tumor Effects of Toosendanin in Glioma Cells

“…Apoptosis is known as a form of programmed cell death, and its inhibition leads to unlimited growth of tumor cells [30]. Previous studies have shown that TSN can induce tumor cell apoptosis [15,23]. These results were consistent with our nding that TSN-induced apoptosis is achieved through the activation of a cascade of reactions including the caspase cascade and increased ratio of Bax/Bcl-2.…”

“…Studies have recently shown the anti-tumor effects of TSN on different types of malignant tumors [21]; however, the role of TSN in glioma remains unclear. Studies regarding the anti-glioma role of TSN are limited; however, few have shown that the mechanism involves the p53 and mir-608/notch axis [22,23]. For the rst time, we propose the role of TSN in the inhibition of the viability and metastasis of glioma cells through the promotion of induced apoptosis and inhibition of the PI3K/Akt/mTOR pathway.…”

Limonoids From the Genus Melia (Meliaceae): Phytochemistry, Synthesis, Bioactivities, Pharmacokinetics, and Toxicology

“…The results also found that, apart from decreased cyclin D1 and increased p21, the expression of p53, a G1-phase checkpoint-associated protein, increased as well ( Wang et al, 2020b ). In addition, cell cycle arrest also occurred in other tumor cells, such as glioblastoma ( Wang Q. et al, 2020 ) and leukemia ( Ju et al, 2013 ).…”