Delayed growth of glioma by Scutellaria flavonoids involve inhibition of Akt, GSK-3 and NF-κB signaling.
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.
Parajuli
Prahlad
P
Department of Neurosurgery, Wayne State University & Karmanos Cancer Institute, Detroit, MI, 48201, USA. pparajuli@med.wayne.edu
Joshee
N
N
Chinni
S R
SR
Rimando
A M
AM
Mittal
S
S
Sethi
S
S
Yadav
A K
AK
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D005419:Flavonoids / Q000627:therapeutic use*; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D047468:Immunoprecipitation; D016328:NF-kappa B / Q000378:metabolism; D008517:Phytotherapy / Q000379:methods*; D010936:Plant Extracts / Q000627:therapeutic use; D018515:Plant Leaves / Q000737:chemistry; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D031363:Scutellaria / Q000737:chemistry*; D015398:Signal Transduction / Q000187:drug effects*
D000970:Antineoplastic Agents; D005419:Flavonoids; D016328:NF-kappa B; D010936:Plant Extracts; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3
Clin Cancer Res. 2002 Apr;8(4):1228-36
11948137
Eur J Pharmacol. 2008 Sep 4;591(1-3):7-12
18577379
Nat Rev Drug Discov. 2005 Dec;4(12):988-1004
16341064
Mol Nutr Food Res. 2008 Nov;52(11):1349-57
18496814
Mol Cell Biol. 2002 Jan;22(2):680-91
11756562
Phytomedicine. 2006 Feb;13(3):205-8
16428031
Int J Cancer. 2008 Feb 15;122(4):816-22
17957784
Am J Clin Nutr. 2001 Oct;74(4):418-25
11566638
Curr Neurol Neurosci Rep. 2008 May;8(3):264-8
18541122
Semin Radiat Oncol. 2010 Jan;20(1):58-66
19959032
Proc Natl Acad Sci U S A. 1977 Jul;74(7):3065-7
197531
Planta Med. 2009 Jan;75(1):41-8
19031366
Neurosurgery. 2004 Dec;55(6):1410-9; discussion 1419
15574223
Nat Clin Pract Neurol. 2007 Dec;3(12):682-93
18046441
Free Radic Biol Med. 2002 Dec 15;33(12):1693-702
12488137
J Natl Cancer Inst. 1959 Apr;22(4):719-48
13655060
J Chromatogr B Biomed Sci Appl. 1998 Sep 4;714(2):369-74
9766878
Breast Cancer Res Treat. 2007 Sep;105(1):17-28
17111207
PLoS One. 2009 Oct 13;4(10):e7443
19823589
BMC Complement Altern Med. 2006 Aug 16;6:27
16914050
Blood. 2006 Dec 1;108(12):3700-6
16931628
Cancer Res. 2008 Aug 15;68(16):6643-51
18701488
Neuroscience. 2006 Jun 30;140(2):477-89
16580779
Blood. 2008 Feb 15;111(4):2354-63
18070986
Phytomedicine. 2003 Nov;10(8):640-9
14692724
Oncogene. 2005 Nov 14;24(50):7482-92
16288295
Expert Opin Biol Ther. 2007 Apr;7(4):439-48
17373896
Nature. 1999 Sep 2;401(6748):86-90
10485711
Can J Neurol Sci. 2007 Aug;34(3):296-306
17803026
J Biol Chem. 2002 Nov 1;277(44):41888-96
12167628
Nature. 1999 Sep 2;401(6748):82-5
10485710
Clin Cancer Res. 2009 Feb 1;15(3):887-97
19188159
Cancer Treat Rev. 2009 Feb;35(1):57-68
19004559
Biosci Biotechnol Biochem. 2006 Oct;70(10):2371-80
17031041
J Neurosurg. 2001 Sep;95(3):480-8
11565871