title: Anticancer action of garcinol in vitro and in vivo is in part mediated through inhibition of STAT-3 signaling.
abstract: Garcinol, obtained from Garcinia indica, has exhibited some promising anticancer activity. In particular, our earlier work has demonstrated its ability to inhibit cell proliferation and induction of apoptosis in multiple cancer cell lines representative of breast, prostate, as well as pancreatic cancers. However, its exact mechanism of action remains largely unclear. Here we show that garcinol also targets signal transducer and activator of transcription-3 (STAT-3) signaling pathway. STAT-3 is frequently found to be activated in many cancer types and this is the first report on such action of garcinol leading to its anticancer effects. Garcinol inhibited total, as well as phosphorylated, STAT-3 in breast, prostate and pancreatic cancer cell lines and was also found to inhibit cell invasion of all the cancer cell lines tested. STAT-3 phosphorylation was inhibited by garcinol in a dose-dependent manner. We also observed an inhibitory effect of garcinol on IL-6-induced STAT-3 phosphorylation and production of urokinase-type plasminogen activator, vascular endothelial growth factor and matrix metalloproteinase-9, which might explain the reduced invasion and aggressiveness of cells treated with garcinol. The results were further verified in vivo using MDA-MB-231 breast cancer mouse xenograft model where administration of garcinol significantly inhibited tumor growth, and western blot analysis of remnant tumor lysates showed reduced STAT-3 expression and activation. These results suggest that garcinol may have translational potential as chemopreventive or therapeutic agent against multiple cancers and inhibition of STAT-3 signaling pathway is one of the mechanisms by which garcinol exerts its anticancer effects.
authors.affiliation: Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, 4100 John R. Street, Detroit, MI 48201, USA.
authors.forename: Aamir
authors.initials: A
authors.lastname: Ahmad
authors.forename: Sanila H
authors.initials: SH
authors.lastname: Sarkar
authors.forename: Amro
authors.initials: A
authors.lastname: Aboukameel
authors.forename: Shadan
authors.initials: S
authors.lastname: Ali
authors.forename: Bernhard
authors.initials: B
authors.lastname: Biersack
authors.forename: Sebastian
authors.initials: S
authors.lastname: Seibt
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Li
authors.forename: Bin
authors.initials: B
authors.lastname: Bao
authors.forename: Dejuan
authors.initials: D
authors.lastname: Kong
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Banerjee
authors.forename: Rainer
authors.initials: R
authors.lastname: Schobert
authors.forename: Subhash B
authors.initials: SB
authors.lastname: Padhye
authors.forename: Fazlul H
authors.initials: FH
authors.lastname: Sarkar
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D017606:Chlorine Compounds / Q000494:pharmacology; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D016328:NF-kappa B / Q000502:physiology; D009361:Neoplasm Invasiveness; D017671:Platinum Compounds / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*; D013729:Terpenes / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D017606:Chlorine Compounds; D015850:Interleukin-6; D016328:NF-kappa B; D017671:Platinum Compounds; D050796:STAT3 Transcription Factor; D013729:Terpenes; C529200:trichloronitritodiammineplatinum(IV); C054597:garcinol