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

Yap WN, Chang PN, Han HY, Lee DT, Ling MT, Wong YC, Yap YL - Br. J. Cancer (2008)

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: Davos Life Science Pte. Ltd., Cancer Research Laboratory, 11 Biopolis way, #07-03, The Helios 138667, Singapore.

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 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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Synergistic effect of γ-T3 on Docetaxel-induced apoptosis. (A) Effect of Docetaxel and γ-T3 co-treatment for 24-h. Cells were incubated with different dosages of γ-T3 and 100 nM of Docetaxel for 24 h. Cell viability was examined by MTT assay. The percentage of apoptotic PC-3 and LNCaP cells following co-treatment of Docetaxel and γ-T3 was significantly higher than that treated with either agent alone. (B) Using western blotting, we further demonstrated that γ-T3 co-treatment with Docetaxel for 24-h enhances PC-3 cell apoptosis through activation of pro-apoptotic molecules (cleaved PARP, caspases 3, 7, 8, 9). Additional suppression of proliferation genes were also confirmed for Id-1, EGF-R, iκB, and NF-κB p65. (C) Proposed T3 anticancer pathway in PCa cells.
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fig5: Synergistic effect of γ-T3 on Docetaxel-induced apoptosis. (A) Effect of Docetaxel and γ-T3 co-treatment for 24-h. Cells were incubated with different dosages of γ-T3 and 100 nM of Docetaxel for 24 h. Cell viability was examined by MTT assay. The percentage of apoptotic PC-3 and LNCaP cells following co-treatment of Docetaxel and γ-T3 was significantly higher than that treated with either agent alone. (B) Using western blotting, we further demonstrated that γ-T3 co-treatment with Docetaxel for 24-h enhances PC-3 cell apoptosis through activation of pro-apoptotic molecules (cleaved PARP, caspases 3, 7, 8, 9). Additional suppression of proliferation genes were also confirmed for Id-1, EGF-R, iκB, and NF-κB p65. (C) Proposed T3 anticancer pathway in PCa cells.

Mentions: Many of the natural products, such as aged garlic extract (Howard et al, 2007) or lupeol (Prasad et al, 2008) which are extracted from fruit or plant have been shown to have a chemosensitisation effect. Although it is not clear if γ-T3 may affect the sensitivity of cancer cells to chemotherapy, previous study has shown that it did enhance the effectiveness of radiation treatment against prostate tumour (Kumar et al, 2006). To test if γ-T3 can act synergistically with a chemotherapeutic agent, we have compared the effect of γ-T3 alone or in combination with Docetaxel. As shown in Figure 5A, the percentage of apoptotic cells in PC-3 and LNCaP cell lines following co-treatment of Docetaxel with γ-T3 for 24 h was significantly higher than that treated with γ-T3 or Docetaxel alone. Using western blotting, we further demonstrated that γ-T3 co-treatment with Docetaxel enhances cell apoptosis through activation of pro-apoptotic proteins (cleaved PARP, caspases 3, 7, 8, 9) and downregulation of pro-survival proteins (Id-1, EGF-R, iκB and NF-κB p65) (Figure 5B). The level of apoptotic cells is in stark contrast to the γ-T co-treatment with Docetaxel. These results suggested that γ-T3 and Docetaxel might have a synergistic effect against prostate cancer cells.


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

Yap WN, Chang PN, Han HY, Lee DT, Ling MT, Wong YC, Yap YL - Br. J. Cancer (2008)

Synergistic effect of γ-T3 on Docetaxel-induced apoptosis. (A) Effect of Docetaxel and γ-T3 co-treatment for 24-h. Cells were incubated with different dosages of γ-T3 and 100 nM of Docetaxel for 24 h. Cell viability was examined by MTT assay. The percentage of apoptotic PC-3 and LNCaP cells following co-treatment of Docetaxel and γ-T3 was significantly higher than that treated with either agent alone. (B) Using western blotting, we further demonstrated that γ-T3 co-treatment with Docetaxel for 24-h enhances PC-3 cell apoptosis through activation of pro-apoptotic molecules (cleaved PARP, caspases 3, 7, 8, 9). Additional suppression of proliferation genes were also confirmed for Id-1, EGF-R, iκB, and NF-κB p65. (C) Proposed T3 anticancer pathway in PCa cells.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2600692&req=5

fig5: Synergistic effect of γ-T3 on Docetaxel-induced apoptosis. (A) Effect of Docetaxel and γ-T3 co-treatment for 24-h. Cells were incubated with different dosages of γ-T3 and 100 nM of Docetaxel for 24 h. Cell viability was examined by MTT assay. The percentage of apoptotic PC-3 and LNCaP cells following co-treatment of Docetaxel and γ-T3 was significantly higher than that treated with either agent alone. (B) Using western blotting, we further demonstrated that γ-T3 co-treatment with Docetaxel for 24-h enhances PC-3 cell apoptosis through activation of pro-apoptotic molecules (cleaved PARP, caspases 3, 7, 8, 9). Additional suppression of proliferation genes were also confirmed for Id-1, EGF-R, iκB, and NF-κB p65. (C) Proposed T3 anticancer pathway in PCa cells.
Mentions: Many of the natural products, such as aged garlic extract (Howard et al, 2007) or lupeol (Prasad et al, 2008) which are extracted from fruit or plant have been shown to have a chemosensitisation effect. Although it is not clear if γ-T3 may affect the sensitivity of cancer cells to chemotherapy, previous study has shown that it did enhance the effectiveness of radiation treatment against prostate tumour (Kumar et al, 2006). To test if γ-T3 can act synergistically with a chemotherapeutic agent, we have compared the effect of γ-T3 alone or in combination with Docetaxel. As shown in Figure 5A, the percentage of apoptotic cells in PC-3 and LNCaP cell lines following co-treatment of Docetaxel with γ-T3 for 24 h was significantly higher than that treated with γ-T3 or Docetaxel alone. Using western blotting, we further demonstrated that γ-T3 co-treatment with Docetaxel enhances cell apoptosis through activation of pro-apoptotic proteins (cleaved PARP, caspases 3, 7, 8, 9) and downregulation of pro-survival proteins (Id-1, EGF-R, iκB and NF-κB p65) (Figure 5B). The level of apoptotic cells is in stark contrast to the γ-T co-treatment with Docetaxel. These results suggested that γ-T3 and Docetaxel might have a synergistic effect against prostate cancer cells.

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: Davos Life Science Pte. Ltd., Cancer Research Laboratory, 11 Biopolis way, #07-03, The Helios 138667, Singapore.

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 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.

Show MeSH
Related in: MedlinePlus