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Title: Delayed growth of glioma by Scutellaria flavonoids involve inhibition of Akt GSK-3 and NF-kB signaling

Author
item PARAJULI, PRAHLAD - Wayne State University
item JOSHEE, NIRMAL - Fort Valley State University
item CHINNI, SREENIVASA - Wayne State University
item Rimando, Agnes
item MITTAL, SANDEEP - Wayne State University
item SETHI, SEEMA - Wayne State University
item YADAV, ANAND - Fort Valley State University

Submitted to: Journal of Neuro-Oncology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/30/2010
Publication Date: 1/14/2011
Citation: Parajuli, P., Joshee, N., Chinni, S.R., Rimando, A.M., Mittal, S., Sethi, S., Yadav, A.K. 2011. Delayed growth of glioma by Scutellaria flavonoids involve inhibition of Akt, GSK-3 and NF-kB signaling. Journal of Neuro-Oncology. 101:15-24.

Interpretive Summary: Plants of the genus Scutellaria constitute one of the common components of Eastern as well as traditional American medicine against various human diseases, including cancer. In this study, we examined the activity of a leaf extract of Scutellaria ocmulgee (SocL) in inhibiting brain tumor cells, and also explored possible mechanisms of action. Oral administration of SocL extract delayed the growth of tumor cells in the rat models. Analysis of the tumors in the animals treated with SocL extract showed inhibition of some proteins involved in cell signaling pathway and a protein complex that controls transcription of DNA. In vitro studies using brain tumor cells demonstrated that SocL extract, as well as the Scutellaria flavonoid wogonin, specifically bind to and inhibit the activity of the signaling molecule Akt. This study provides the first in vivo evidence and mechanistic support of the activity of Scutellaria against brain tumors.

Technical Abstract: Plants of the genus Scutellaria constitute one of the common components of Eastern as well as traditional American medicine against various human diseases, including cancer. In this study, we examined the in vivo anti-glioma activity of a leaf extract of Scutellaria ocmulgee (SocL) while also exploring their potential molecular mechanisms of action. Oral administration of SocL extract delayed the growth of F98 glioma in F344 rats, both in intracranial and subcutaneous tumor models. Immunohistochemistry revealed inhibition of Akt, GSK-3a/B and NF-kB phosphorylation in the subcutaneous tumors following treatment with Scutellaria. The SocL extract as well as the constituent flavonoid wogonin also showed dose- and time-dependent inhibition of Akt, GSK-3a/B and NF-kB in F98 cell cultures in vitro, as determined by Western blot analysis. Pharmacologic inhibitors of PI3K and NF-kB also significantly inhibited the in vitro proliferation of F98 glioma cells, indicating the key role of these signaling molecules in the growth of malignant gliomas. Transfection of F98 cells with constitutively active mutant of AKT (AKT/CA), however, did not significantly reverse Scutellaria-mediated inhibition of proliferation, indicating that Scutellaria flavonoids either directly inhibited Akt kinase activity or acted downstream of Akt. In vitro Akt kinase assay demonstrated that the SocL extract or wogonin could indeed bind to Akt and inhibit its kinase activity. This study provides the first in vivo evidence and mechanistic support for anti-glioma activity of Scutellaria flavonoids and has implications in potential usage of Scutellaria flavonoids in adjuvant therapy for malignant tumors, including gliomas.