γ‐Tocotrienol is a novel inhibitor of constitutive and inducible STAT3 signalling pathway in human hepatocellular carcinoma: potential role as an antiproliferative, pro‐apoptotic and chemosensitizing agent

Abstract

BACKGROUND AND PURPOSEActivation of signal transducer and activator of transcription 3 (STAT3) play a critical role in the survival, proliferation, angiogenesis and chemoresistance of tumour cells. Thus, agents that suppress STAT3 phosphorylation have potential as cancer therapies. In the present study, we investigated whether the apoptotic, antiproliferative and chemosensitizing effects of g-tocotrienol are associated with its ability to suppress STAT3 activation in hepatocellular carcinoma (HCC). EXPERIMENTAL APPROACHThe effect of g-tocotrienol on STAT3 activation, associated protein kinases and phosphatase, STAT3-regulated gene products, cellular proliferation and apoptosis in HCC cells was investigated. KEY RESULTSg-Tocotrienol inhibited both the constitutive and inducible activation of STAT3 with minimum effect on STAT5. g-Tocotrienol also inhibited the activation of Src, JAK1 and JAK2 implicated in STAT3 activation. Pervanadate reversed the g-tocotrienolinduced down-regulation of STAT3, suggesting the involvement of a protein tyrosine phosphatase. Indeed, we found that g-tocotrienol induced the expression of the tyrosine phosphatase SHP-1 and deletion of the SHP-1 gene by small interfering RNA abolished the ability of g-tocotrienol to inhibit STAT3 activation. g-Tocotrienol also down-regulated the expression of STAT3-regulated gene products, including cyclin D1, Bcl-2, Bcl-xL, survivin, Mcl-1 and vascular endothelial growth factor. Finally, g-tocotrienol inhibited proliferation, induced apoptosis and significantly potentiated the apoptotic effects of chemotherapeutic drugs (paclitaxel and doxorubicin) used for the treatment of HCC. CONCLUSIONS AND IMPLICATIONSOverall, these results suggest that g-tocotrienol is a novel blocker of the STAT3 activation pathway, with a potential role in future therapies for HCC and other cancers. BJPBritish Journal of Pharmacology DOI:10.1111DOI:10. /j.1476DOI:10. -5381.2010 British Journal of Pharmacology (2011) IntroductionHepatocellular carcinoma (HCC) is the fifth most common cancer in the world, with an estimated incidence of half a million new cases per year around the world (El-Serag and Rudolph, 2007;Berasain et al., 2009). The HCC is characterized as a highly chemoresistant cancer with several aetiological factors being classified as high-risk factors, including exposure to aflatoxin B1, and infection with hepatitis B virus and hepatitis C virus (Kern et al., 2002;Farazi and DePinho, 2006). First line chemotherapeutic drugs currently being used for HCC therapy include doxorubicin, fluorouracil, cisplatin, and mitomycin, but most of these exhibit significant side effects (Avila et al., 2006;Kerr and Kerr, 2009;Rampone et al., 2009). Therefore, the need to develop more therapeutic strategies for HCC that are non-toxic and efficacious is of paramount importance. Anticancer drug discovery from agents derived from natural sources provides a great opportunity to improve the existing standard of care for HCC and other cancers (Newman, 2008). One such agent is, g-tocotrieno...

Dietary compounds as potent inhibitors of the signal transducers and activators of transcription (STAT) 3 regulatory network

“…Therefore, it is very important to identify new effective drugs. Among natural compounds from a variety of plants, diosgenin , b-escin (Tan et al 2010), butein ) and c-tocotrienol (Rajendran et al 2011a) were reported to inhibit proliferation and to induce apoptosis of HCC cells concomitantly in order to downregulate various STAT3-regulated gene products, including cyclin D1, Bcl-2, Bcl-xL, survivin, Mcl-1 and VEGF. These four natural molecules inhibited constitutive and inducible activation of STAT3 through the inhibition of c-Src, JAK1 and JAK2 activation.…”

Potential role of signal transducer and activator of transcription (STAT)3 signaling pathway in inflammation, survival, proliferation and invasion of hepatocellular carcinoma

“…Natural agents, peptides, platinum compounds and other small molecules have been used to inhibit STAT3 activity in various tumor models including HCC [258]. Our group has identified number of STAT3 inhibitors including diosgenin, β-escin, γ-tocotrienol, butein, honokiol, and celastrol that can suppress growth and induce apoptosis in diverse HCC cell lines [259][260][261][262][263][264]. In addition, Chen and coworkers recently reported that a novel obatoclax derivative, SC-2001, can induce apoptosis in hepatocellular carcinoma cells through SHP-1-dependent STAT3 inactivation [265].…”

First Evidence That γ-Tocotrienol Inhibits the Growth of Human Gastric Cancer and Chemosensitizes It to Capecitabine in a Xenograft Mouse Model through the Modulation of NF-κB Pathway

“…The effect of g-tocotrienol on cell proliferation was determined by the MTT uptake method as described previously (20). The cells (5,000 per well) were incubated with g-tocotrienol in triplicate in a 96-well plate and then incubated for indicated time points at 37…”

“…However, while tocopherols had been intensively studied for their health benefits, many novel benefits of tocotrienols are only beginning to be brought to light by research in the last decade (13,14). For instance, g-tocotrienol has been reported to suppress the proliferation of a wide variety of tumor cells (15), including gastric (16)(17)(18)(19), hepatocellular carcinoma (20), melanoma (21), breast (22), colorectal (23), and prostate (24). In vivo mice studies have shown that g-tocotrienol can suppress the growth of breast tumor (25), prostate (26), lung cancer and melanoma (27) and also inhibit the growth of liver and pancreatic cancer either alone or in combination with chemotherapeutic drugs and radiation (28,29).…”

“…In vivo mice studies have shown that g-tocotrienol can suppress the growth of breast tumor (25), prostate (26), lung cancer and melanoma (27) and also inhibit the growth of liver and pancreatic cancer either alone or in combination with chemotherapeutic drugs and radiation (28,29). How g-tocotrienol mediates its anticancer effects is not completely understood, but the roles of various signaling cascades/kinases/transcription factors such as mitogen-activated protein kinases (17), phosphoinositide 3-kinase (PI3K)/Akt (30), NF-kB (13), STAT3 (20), telomerase (31), PPAR-g (32), hypoxiainducible factor-1a (33), b-catenin (23), EGF (24), and inhibitor of differentiation family proteins (34) have been implicated.…”