title: Scutellaria extract and wogonin inhibit tumor-mediated induction of T(reg) cells via inhibition of TGF-β1 activity.
abstract: A number of studies have implicated tumor-induced T(reg) cell activity in the sub-optimal response to therapeutic vaccines. Development of neo-adjuvant strategies targeting T(reg) cells is therefore imperative. Scutellaria extracts or constituent flavonoids have shown encouraging efficacy against various tumors, including gliomas, in both pre-clinical and clinical studies. We report here, for the first time, that Scutellaria ocmulgee leaf extract (SocL) and flavonoid wogonin could inhibit TGF-β1-induced T(reg) activity in malignant gliomas. F344 rats, subcutaneously transplanted with F98 gliomas, were treated with SocL. There was a significant inhibition of intra-tumoral TGF-β1 and T(reg) cell frequency as well as peripheral blood TGF-β1 levels in SocL-treated animals compared to the controls. SocL extract and wogonin also inhibited glioma-induced, TGF-β1-mediated T(reg) activity in vitro. SocL extract and wogonin also inhibited the secretion of IL-10 in T(reg) culture; whereas the level of IL-2 was either unchanged or marginally enhanced. We also observed an inhibition of Smad-3, GSK-3β and ERK1/2 signaling by SocL and wogonin in T(reg) cells, while phosphorylation of P38 MAPK was considerably enhanced, indicating that SocL or wogonin could inhibit the T cells' response to TGF-β1 via modulation of both Smad and non-Smad signaling pathways. Overall, this study suggests that Scutellaria can potentially reverse tumor-mediated immune suppression via inhibition of TGF-β1 secretion as well as via inhibition of T cells' response to TGF-β1. This may provide an opportunity for developing a novel adjuvant therapeutic strategy for malignant gliomas, combining Scutellaria with immunotherapy and chemo/radio-therapeutic regimen, which could potentially improve the disease outcome.
authors: Department of Neurosurgery, Wayne State University, Detroit, MI 48201, USA. dandawatesagar09@gmail.com
authors: Sagar
authors: S
authors: Dandawate
authors: Linford
authors: L
authors: Williams
authors: Nirmal
authors: N
authors: Joshee
authors: Agnes M
authors: AM
authors: Rimando
authors: Sandeep
authors: S
authors: Mittal
authors: Archana
authors: A
authors: Thakur
authors: Lawrence G
authors: LG
authors: Lum
authors: Prahlad
authors: P
authors: Parajuli
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D044950:Flavanones / Q000276:immunology / Q000494:pharmacology*; D005910:Glioma / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000276:immunology; D000071679:Glycogen Synthase Kinase 3 beta; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000276:immunology; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D010936:Plant Extracts / Q000276:immunology / Q000494:pharmacology*; D018515:Plant Leaves / Q000737:chemistry; D051381:Rats; D031363:Scutellaria / Q000737:chemistry*; D015398:Signal Transduction; D051900:Smad3 Protein / Q000037:antagonists & inhibitors / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology
chemical_list: D044950:Flavanones; D007376:Interleukin-2; D010936:Plant Extracts; D051900:Smad3 Protein; C497787:Smad3 protein, rat; D053773:Transforming Growth Factor beta1; D016753:Interleukin-10; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D048051:p38 Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; C085514:wogonin