1. ¹Davos Life Science Pte. Ltd., Cancer Research Laboratory, 11 Biopolis way, #07-03, The Helios 138667, Singapore
2. ²Department of Anatomy, Cancer Biology Lab, Li Ka Shing Faculty of Medicine, The University of Hong Kong (HKU), 1/F, Laboratory Block, 21 Sassoon Road, Hong Kong SAR

Correspondence: Dr YL Yap, E-mail: daniel.yap@davoslife.com; Dr YC Wong, E-mail: ycwong@hkucc.hku.hk; Dr MT Ling, E-mail: patling@hkucc.hku.hk

Received 9 September 2008; Revised 30 September 2008; Accepted 6 October 2008; Published online 11 November 2008.

Abstract

Tocotrienol-rich fraction (TRF) has demonstrated antiproliferative effect on prostate cancer (PCa) cells. To elucidate this anticancer property in PCa cells, this study aimed, first, to identify the most potent isomer for eliminating PCa cells; and second, to decipher the molecular pathway responsible for its activity. Results showed that the inhibitory effect of -tocotrienol was most potent, which resulted in induction of apoptosis as evidenced by activation of pro-caspases and the presence of sub-G₁ cell population. Examination of the pro-survival genes revealed that the -tocotrienol-induced cell death was associated with suppression of NF-B, EGF-R and Id family proteins (Id1 and Id3). Meanwhile, -tocotrienol treatment also resulted in the induction of JNK-signalling pathway and inhibition of JNK activity by a specific inhibitor (SP600125) was able to partially block the effect of -tocotrienol. Interestingly, -tocotrienol treatment led to suppression of mesenchymal markers and the restoration of E-cadherin and -catenin expression, which was associated with suppression of cell invasion capability. Furthermore, a synergistic effect was observed when cells were co-treated with -tocotrienol and Docetaxel. Our results suggested that the antiproliferative effect of -tocotrienol act through multiple-signalling pathways, and demonstrated for the first time the anti-invasion and chemosensitisation effect of -tocotrienol against PCa cells.