In vivo Evidence of γ-Tocotrienol as a Chemosensitizer in the Treatment of Hormone-Refractory Prostate Cancer

W.N. Yap^a, N. Zaiden^a, S.Y. Luk^b, D.T.W. Lee^b, M.T. Ling^c, Y.C. Wong^b and Y.L. Yap^a
^aDavos Life Science, Cancer Research Laboratory, Singapore , Singapore
^bLi Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong , China
^cAustralian Prostate Cancer Research Centre – Queensland Institute of Health and Biomedical Innovation, Brisbane, Qld. , Australia

Pharmacology 2010;85:248–258
DOI: 10.1159/000278205
www.bjcancer.com
Published online: April 7, 2010

Abstract:

γ-Tocotrienol (γT3) is known to selectively kill prostate cancer (PCa) cells and to sensitize the cells to docetaxel (DTX)induced apoptosis. In the present study, the pharmacokinetics of γT3 and the in vivo cytotoxic response of androgen-independent prostate cancer (AIPCa) tumor following γT3 treatment were investigated. Here, we investigated these antitumor effects for PCa tumors in vivo. The pharmacokinetic and tissue distribution of γT3 after exogenous γT3 supplementation were examined. Meanwhile, the response of the tumor to γT3 alone or in combination with DTX were studied by real-time in vivo bioluminescent imaging and by examination of biomarkers associated with cell proliferation and apoptosis. After intraperitoneal injection, γT3 rapidly disappeared from the serum and was selectively deposited in the AIPCa tumor cells. Administration of γT3 alone for 2 weeks resulted in a significant shrinkage of the AIPCa tumors. Meanwhile, further inhibition of the AIPCa tumor growth was achieved by combined treatment of γT3 and DTX (p<0.002). The in vivo cytotoxic antitumor effects induced by γT3 seem to be associated with a decrease in expression of cell proliferation markers (proliferating cell nuclear antigen, Ki-67 and Id1) and an increase in the rate of cancer cell apoptosis [cleaved caspase 3 and poly(ADP-ribose) polymerase]. Additionally, the combined agents may be more effective at suppressing the invasiveness of AIPCa. Overall, our results indicate that γT3, either alone or in combination with DTX, may provide a treatment strategy that can improve therapeutic efficacy against AIPCa while reducing the toxicity often seen in patients treated with DTX.

Keywords:

Tocotrienol, Vitamin E, Prostate cancer, Docetaxel, Chemotherapy