Delta-tocotrienol acts as a chemosensitizing agent. - GreenMedInfo Summary
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.
Br J Pharmacol. 2010 Dec 30. Epub 2010 Dec 30. PMID: 21198544
Departments of Pharmacology and Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, and Cancer Science Institute of Singapore, National University of Singapore, 28 Medical Drive, Singapore 117456.
Background and Purpose: Activation of signal transducers 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, anti-proliferative and chemosensitizing effects ofγ-tocotrienol are associated with its ability to suppress STAT3 phosphorylation in hepatocellular carcinoma (HCC). Experimental approach: The effect of γ-tocotrienol on STAT3 activation, associated protein kinases and phosphatase, STAT3-regulated gene products, cellular proliferation and apoptosisin HCC cells was investigated. Key Results: γ-Tocotrienol inhibited both the constitutive and inducible activation of STAT3 with minimum effect on STAT5. γ-Tocotrienol also inhibited the activation of c-Src, JAK1 and JAK2 implicated in STAT3 activation. Pervanadate reversed the γ-tocotrienol -induced downregulation of STAT3, suggesting the involvement of a protein tyrosine phosphatase. Indeed, we found that γ-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 γ-tocotrienol to inhibit STAT3activation. γ-Tocotrienol also downregulated the expression of STAT3-regulated gene products, including cyclin D1, Bcl-2, Bcl-xL, survivin, Mcl-1 and vascular endothelial growth factor. Finally, γ-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 Implications: Overall, these results suggest that γ-tocotrienol is a novel blocker of the STAT3 activation pathway, with a potential role in future therapies for HCC and other cancers.