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Delayed growth of glioma by Scutellaria flavonoids involve inhibition of Akt, GSK-3 and NF-κB signaling

  • Laboratory Investigation - Human/Animal Tissue
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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-3α/β and NF-κB 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-3α/β and NF-κB in F98 cell cultures in vitro, as determined by western blot analysis. Pharmacologic inhibitors of PI3K and NF-κB 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.

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Abbreviations

CA:

Constitutively active

DN:

Dominant negative (mutant)

GSK:

Glycogen synthase kinase

NF-κB:

Nuclear factor-κB

SocL:

Scutellaria ocmulgee leaf (extract)

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Acknowledgements

We acknowledge research grant from the Fund for Medical Research and Education (FMRE), to PP and the USDA-CSREES Research Project # 2008-02492 (Award # 2008-38814-04737) to NJ (PD), PP and AKY (Co-PD’s). We are grateful to Dr. Kenneth Walsh, University of Boston, MA for kindly providing us with the AKT plasmid constructs. We thank Chao (Becky) Wong for technical assistance; Dr. Yimin Shen for help with MRI imaging; and Brandon Parker for manuscript editing.

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Authors and Affiliations

  1. Department of Neurosurgery, Wayne State University & Karmanos Cancer Institute, 4100 John R. St., HW-CRC #607, Detroit, MI, 48201, USA

    Prahlad Parajuli & S. Mittal

  2. Agricultural Research Station, Fort Valley State University, Fort Valley, GA, USA

    N. Joshee & A. K. Yadav

  3. Department of Urology, Wayne State University, Detroit, MI, USA

    S. R. Chinni

  4. USDA-ARS, Natural Products Utilization Research Unit, University, MS, USA

    A. M. Rimando

  5. Department of Pathology, Wayne State University, Detroit, MI, USA

    S. Sethi

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  1. Prahlad Parajuli
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  2. N. Joshee
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  4. A. M. Rimando
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  5. S. Mittal
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  7. A. K. Yadav
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Correspondence to Prahlad Parajuli.

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Parajuli, P., Joshee, N., Chinni, S.R. et al. Delayed growth of glioma by Scutellaria flavonoids involve inhibition of Akt, GSK-3 and NF-κB signaling. J Neurooncol 101, 15–24 (2011). https://doi.org/10.1007/s11060-010-0221-x

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  • DOI: https://doi.org/10.1007/s11060-010-0221-x

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