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A Multi-targeted Natural Flavonoid Myricetin Suppresses Lamellipodia and Focal Adhesions Formation and Impedes Glioblastoma Cell Invasiveness and Abnormal Motility

[ Vol. 17 , Issue. 7 ]

Author(s):

Hua-Fu Zhao, Gang Wang, Chang-Peng Wu, Xiu-Ming Zhou, Jing Wang, Zhong-Ping Chen, Shing-Shun Tony To* and Wei-Ping Li*   Pages 557 - 567 ( 11 )

Abstract:


Background: Glioblastoma multiforme (GBM) is the most aggressive and malignant primary brain tumor characterized by rapid growth and extensive infiltration to neighboring normal brain parenchyma, which contribute to tumor recurrence and poor prognosis. Myricetin is a natural flavonoid with potent anti-oxidant, anti-inflammatory and anti-cancer activities, which may serve as a potential and harmless agent for GBM treatment.

Methods: To investigate the anti-glioblastoma effects of myricetin, GBM cells were treated with myricetin alone or in combination with temozolomide. Its effects on GBM cell motility and cytoskeletal structures including lamellipodia, focal adhesions and membrane ruffles were also evaluated.

Results: We showed that myricetin alone inhibited glioblastoma U-87 MG cell proliferation, migration and invasion, whereas combination of myricetin and temozolomide did not exhibit any synergistic effect. The inhibitory effect on GBM cell proliferation is independent of PTEN status. Moreover, myricetin showed less cytotoxicity to normal astrocytes than GBM cells. Formation of lamellipodia, focal adhesions, membrane ruffles and vasculogenic mimicry were blocked by myricetin, and phosphorylation of ROCK2, paxillin and cortactin was suppressed. In addition, myricetin could inhibit PI3K/Akt and JNK signaling, and bind to a series of kinases and scaffold proteins including PI3K catalytic isoforms (p110α, p110β and p110δ), PDK1, JNK, c-Jun, ROCK2, paxillin, vinculin and VEcadherin.

Conclusions: In conclusion, myricetin is a multi-targeted drug that has potent anti-migratory and antiinvasive effects on GBM cells, and suppresses formation of lamellipodia and focal adhesions, suggesting that it may serve as an alternative option for GBM treatment.

Keywords:

Myricetin, glioblastoma, motility, invasiveness, lamellipodia, focal adhesion.

Affiliation:

Department of Neurosurgery and Shenzhen Key Laboratory of Neurosurgery, Shenzhen Second People`s Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen 518035, Department of Pharmaceutics, Shanghai Eighth People`s Hospital, Shanghai 200235, College of Clinical Medicine, Anhui Medical University, Hefei 230032, College of Clinical Medicine, Anhui Medical University, Hefei 230032, Department of Neurosurgery/Neuro-oncology, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, Department of Neurosurgery/Neuro-oncology, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong, Department of Neurosurgery and Shenzhen Key Laboratory of Neurosurgery, Shenzhen Second People`s Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen 518035



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