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.

Garcinol, a Polyisoprenylated Benzophenone Modulates Multiple Proinflammatory Signaling Cascades Leading to the Suppression of Growth and Survival of Head and Neck Carcinoma

“…Our results are consistent with a recent report in which garcinol was found to suppress the activation of STAT3 in breast, prostate, and pancreatic cancer cell lines (15), although the detailed molecular mechanisms underlying its STAT3 inhibitory effects were not elucidated in this study. Also, STAT3 phosphorylation plays a pivotal role in proliferation and survival of tumor cells (42).…”

“…Garcinol has gained much attention in the field of cancer research in recent years, and several reports have shown the antineoplastic and chemopreventive role of garcinol in different cancers, such as leukemia, colorectal, gastrointestinal, and breast cancers (12)(13)(14)(15)(16). Although there is a prior evidence showing that garcinol can inhibit 4-nitroquinoloine 1-oxide-induced tongue carcinogenesis (17), mechanisms through which garcinol elicits its antitumor activity, specifically in HNSCC, is unknown till date.…”

Antidiabetic Effect of Garcinol on Streptozotocin-induced Diabetic Rats

“…Literature revealed that garcinol exhibited antioxidant, antiinflammatory, anticancer and hepatoprotective activities [6][7][8][9] . Garcinol was also reported to exhibit radical scavenging activity and suppressed protein glycation in vitro [5] .…”

Garcinol: Current status of its anti-oxidative, anti-inflammatory and anti-cancer effects

“…Garcinol interferes with multiple signaling cascades to induce apoptosis in several cancer cell lines. The known mechanisms of action of garcinol in apoptosis involve the inactivation of the signal transducer and activator of transcription 3 (STAT-3), NFκB and phosphoinositide 3-kinase (PI3K)/serine/ threonine-specific protein kinase (Akt) signaling pathways [31,38,44]. This inactivation increases the expression of pro-apoptotic gene products (Bax, Bak) over pro-survival gene products (Bcl-xL, Bcl-2, Mcl-1, survivin), the release of cytochrome c into the cytosol, the activation of caspase-3, and thus, the induction of apoptosis [51].…”