Gamma-tocotrienol suppresses prostate cancer cell proliferation and invasion through multiple-signalling pathways

Yap, W. N.,Chang, P. N.,Han, H. Y.,Lee, D. T.,Ling, M. T.,Wong, Y. C.,Yap, Y. L.

Br J Cancer, 2008; 99(11):1832-41

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 gamma-tocotrienol was most potent, which resulted in induction of apoptosis as evidenced by activation of pro-caspases and the presence of sub-G(1) cell population. Examination of the pro-survival genes revealed that the gamma-tocotrienol-induced cell death was associated with suppression of NF-kappaB, EGF-R and Id family proteins (Id1 and Id3). Meanwhile, gamma-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 gamma-tocotrienol. Interestingly, gamma-tocotrienol treatment led to suppression of mesenchymal markers and the restoration of E-cadherin and gamma-catenin expression, which was associated with suppression of cell invasion capability. Furthermore, a synergistic effect was observed when cells were co-treated with gamma-tocotrienol and Docetaxel. Our results suggested that the antiproliferative effect of gamma-tocotrienol act through multiple-signalling pathways, and demonstrated for the first time the anti-invasion and chemosensitisation effect of gamma-tocotrienol against PCa cells.

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Tocotrienol-rich fraction of palm oil induces cell cycle arrest and apoptosis selectively in human prostate cancer cells

Srivastava JK, Gupta S.

Biochem Biophys Res Commun. 2006 Jul 28;346(2):447-53. Epub 2006 Jun 2.

One of the requisite of cancer chemopreventive agent is elimination of damaged or malignant cells through cell cycle inhibition or induction of apoptosis without affecting normal cells. In this study, employing normal human prostate epithelial cells (PrEC), virally transformed normal human prostate epithelial cells (PZ-HPV-7), and human prostate cancer cells (LNCaP, DU145, and PC-3), we evaluated the growth-inhibitory and apoptotic effects of tocotrienol-rich fraction (TRF) extracted from palm oil. TRF treatment to PrEC and PZ-HPV-7 resulted in almost identical growth-inhibitory responses of low magnitude. In sharp contrast, TRF treatment resulted in significant decreases in cell viability and colony formation in all three prostate cancer cell lines. The IC(50) values after 24h TRF treatment in LNCaP, PC-3, and DU145 cells were in the order 16.5, 17.5, and 22.0 microg/ml. TRF treatment resulted in significant apoptosis in all the cell lines as evident from (i) DNA fragmentation, (ii) fluorescence microscopy, and (iii) cell death detection ELISA, whereas the PrEC and PZ-HPV-7 cells did not undergo apoptosis, but showed modestly decreased cell viability only at a high dose of 80 microg/ml. In cell cycle analysis, TRF (10-40 microg/ml) resulted in a dose-dependent G0/G1 phase arrest and sub G1 accumulation in all three cancer cell lines but not in PZ-HPV-7 cells. These results suggest that the palm oil derivative TRF is capable of selectively inhibiting cellular proliferation and accelerating apoptotic events in prostate cancer cells. TRF offers significant promise as a chemopreventive and/or therapeutic agent against prostate cancer.

Preferential radiation sensitization of prostate cancer in nude mice by nutraceutical antioxidant gamma-tocotrienol

Kumar KS, Raghavan M, Hieber K, Ege C, Mog S, Parra N, Hildabrand A, Singh V, Srinivasan V, Toles R, Karikari P, Petrovics G, Seed T, Srivastava S, Papas A.

Life Sci. 2006 Mar 27;78(18):2099-104. Epub 2006 Jan 18.

Gamma-tocotrienol (GT) is a member of the vitamin E family. Our preliminary studies indicated that it protected mice from lethal irradiation, so we hypothesized that GT might be a radiation sensitizing agent for tumors. To test this, we induced prostate tumors by injecting PC3 cells into nude BALB/c mice. When the tumors were about 5 mm in diameter, mice were injected subcutaneously with 400 mg/kg gamma-tocotrienol and irradiated 24 h later at the site of the tumor with a dose of 12 Gy (60)Cobalt. Tumor size was monitored for 24 days after radiation. Tumor tissues as well as normal tissues like rectum, kidney, and liver were monitored for lipid peroxidation on day 4 and day 24 after radiation. The results indicated that the size of the tumors was reduced by almost 40%, but only in GT-treated and irradiated mice. In unstimulated and Fe-stimulated lipid peroxidation groups, lipid peroxidation in the tumors from irradiated mice increased to 135% and 150%, respectively, four days after irradiation and 33% and 66% in the same groups, respectively, 24 days after irradiation. In general, lipid peroxidation in the rectum did not increase in GT-treated and irradiated mice, although there was a slight increase in Fe-stimulated lipid peroxidation (29%) four days after irradiation. Unexpectedly, the kidneys were as equally sensitized to lipid peroxidation as the tumors. Liver tissue was protected in the short-term from radiation-induced lipid peroxidation. These studies indicate that the radiotherapy efficacy of prostate cancer can be increased with GT and a pro-oxidant if the kidneys can be shielded.

Gamma-tocotrienol metabolism and antiproliferative effect in prostate cancer cells

Conte C, Floridi A, Aisa C, Piroddi M, Floridi A, Galli F.

Ann N Y Acad Sci. 2004 Dec;1031:391-4.

In this study, we evaluated the antiproliferative effect of tocotrienols (T3) and the presence of a specific vitamin E metabolism in PC3 and LNCaP prostate cancer cells. These cell lines are able to transform tocopherols (T) and T3 in the corresponding carboxyethyl-hydroxychromans metabolites (CEHCs). The extent of this metabolism and the inhibitory effect on cell growth followed the order of magnitude alpha-T<alpha-T3<gamma-T<gamma-T3. The partial inhibition of gamma-T3 metabolism by ketoconazole did not influence cell proliferation. These early findings may suggest that the transformation of vitamin E to CEHC is mostly a detoxification mechanism useful to maintain the malignant properties of prostate cancer cells.

γ-tocotrienol metabolism and antiproliferative effect in prostate cancer Cells

Carmela Conte, Alessandro Floridi, Cristina Aisa, Marta Piroddi, Ardesio Floridi and Francesco Gall

Ann N Y Acad Sci. 2004 Dec;1031:391-4.

In this study, we evaluated the antiproliferative effect of tocotrienols (T3) and the presence of a specific vitamin E metabolism in PC3 and LNCaP prostate cancer cells. These cell lines are able to transform tocopherols (T) and T3 in the corresponding carboxyethyl-hydroxychromans metabolites (CEHCs). The extent of this metabolism and the inhibitory effect on cell growth followed the order of magnitude α-T<α-T3<γ-T<γ-T3. The partial inhibition of γ-T3 metabolism by ketoconazole did not influence cell proliferation. These early findings may suggest that the transformation of vitamin E to CEHC is mostly a detoxification mechanism useful to maintain the malignant properties of prostate cancer cells.