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Rooibos suppresses proliferation of castration-resistant prostate cancer cells via inhibition of Akt signaling.
Phytomedicine 2019; 64:153068P

Abstract

BACKGROUND

Androgen ablation therapy is the primary treatment for metastatic prostate cancer (PCa). However, the majority of PCa patients receiving the androgen deprivation therapy develop recurrent castration-resistant prostate cancer (CRPC) within two years. Chemotherapies show little effect on prolonging survival of CRPC patients and new treatments are needed. Previous studies reported that the extracts from rooibos (Aspalathus linearis) exhibit chemopreventive properties in some cancer models, including skin, liver and oesophagus cancers in animals. We therefore investigate if extracts from rooibos can suppress the proliferation of CRPC cells.

PURPOSE

We investigated whether an aspalathin-rich green rooibos extract (GRT™; 12.78 g aspalathin/100 g extract) demonstrates anti-cancer activity against CRPC cells.

METHODS

High performance liquid chromatography (HPLC) was used to profile the major flavonoids in GRT. Hoechst-dye proliferation assay, 3,4,5-dimethylthiazol-2-yl)-2-5-diphenyltetrazolium bromide (MTT) viability assay and flow cytometry assay were used to explore the effects of GRT on the proliferation and cell cycle progression of CRPC cells. Comet assay was used to survey whether GRT induces apoptosis in CRPC cells. LNCaP 104-R1 xenograft nude mice model was used to determine the inhibitory effect of GRT on CRPC tumors in vivo. Micro-Western Array (MWA) and Western blot analysis were carried out to unravel the underlying molecular mechanism.

RESULTS

GRT contained aspalathin as the most abundant flavonoid. GRT suppressed the proliferation and survival of LNCaP 104-R1, LNCaP FGC and PC-3 PCa cells. Flow cytometry analysis showed that GRT decreased the population of PCa cells in S phase but increased the cell population in G2/M phase. Comet assay confirmed that GRT induced apoptosis in LNCaP 104-R1 cells. Gavage of 400 mg/kg GRT suppressed LNCaP 104-R1 xenografts in castrated nude mice. MWA and Western blot analysis indicated that GRT treatment suppressed Akt1, phospho-Akt Ser473, Cdc2, Bcl-2, TRAF4 and Aven, but increased activated Caspase 3, cytochrome c, and p27Kip1. Overexpression of Akt rescued the suppressive effects of GRT on CRPC cells. Co-treatment of GRT with Bcl-2 inhibitor ABT-737, PI3K inhibitor LY294002 and Akt inhibitor GSK 690693 exhibited additive inhibitory effect on proliferation of CRPC cells.

CONCLUSIONS

GRT suppresses the proliferation of CRPC cells via inhibition of Akt signaling.

Authors+Show Affiliations

Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli County 35053, Taiwan; Department of Life Sciences, National Central University, Taoyuan City 32001, Taiwan.Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli County 35053, Taiwan.Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli County 35053, Taiwan.Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli County 35053, Taiwan; Institute of Biotechnology, National Tsing Hua University, Hsinchu City 30013, Taiwan.Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli County 35053, Taiwan.Department of Life Sciences, National Central University, Taoyuan City 32001, Taiwan.Biomedical Research and Innovation Platform (BRIP), South African Medical Research Council, Tygerberg 7505, South Africa; Division of Medical Physiology, Faculty of Health Sciences, Stellenbosch University, Tygerberg 7505, South Africa; Department of Biochemistry and Microbiology, University of Zululand, KwaDlangezwa 3886, South Africa.Plant Bioactives Group, Post-Harvest and Agro-Processing Technologies, Agricultural Research Council (ARC), Infruitec-Nietvoorbij, Stellenbosch 7599, South Africa; Department of Food Science, Stellenbosch University, Stellenbosch 7599, South Africa.Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli County 35053, Taiwan; PhD Program for Aging and Graduate Institute of Basic Medical Science, China Medical University, Taichung City 40402, Taiwan; Biotechnology Center, National Chung Hsing University, Taichung City 40227, Taiwan. Electronic address: cpchuu@nhri.org.tw.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31419729

Citation

Huang, Shih-Han, et al. "Rooibos Suppresses Proliferation of Castration-resistant Prostate Cancer Cells Via Inhibition of Akt Signaling." Phytomedicine : International Journal of Phytotherapy and Phytopharmacology, vol. 64, 2019, p. 153068.
Huang SH, Tseng JC, Lin CY, et al. Rooibos suppresses proliferation of castration-resistant prostate cancer cells via inhibition of Akt signaling. Phytomedicine. 2019;64:153068.
Huang, S. H., Tseng, J. C., Lin, C. Y., Kuo, Y. Y., Wang, B. J., Kao, Y. H., ... Chuu, C. P. (2019). Rooibos suppresses proliferation of castration-resistant prostate cancer cells via inhibition of Akt signaling. Phytomedicine : International Journal of Phytotherapy and Phytopharmacology, 64, p. 153068. doi:10.1016/j.phymed.2019.153068.
Huang SH, et al. Rooibos Suppresses Proliferation of Castration-resistant Prostate Cancer Cells Via Inhibition of Akt Signaling. Phytomedicine. 2019 Aug 8;64:153068. PubMed PMID: 31419729.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Rooibos suppresses proliferation of castration-resistant prostate cancer cells via inhibition of Akt signaling. AU - Huang,Shih-Han, AU - Tseng,Jen-Chih, AU - Lin,Ching-Yu, AU - Kuo,Ying-Yu, AU - Wang,Bi-Juan, AU - Kao,Yung-Hsi, AU - Muller,Christo J F, AU - Joubert,Elizabeth, AU - Chuu,Chih-Pin, Y1 - 2019/08/08/ PY - 2019/05/18/received PY - 2019/07/26/revised PY - 2019/08/06/accepted PY - 2019/8/17/pubmed PY - 2019/8/17/medline PY - 2019/8/17/entrez KW - Akt KW - Apoptosis KW - Aspalathin KW - Castration-resistant prostate cancer KW - Micro-Western Array KW - Rooibos SP - 153068 EP - 153068 JF - Phytomedicine : international journal of phytotherapy and phytopharmacology JO - Phytomedicine VL - 64 N2 - BACKGROUND: Androgen ablation therapy is the primary treatment for metastatic prostate cancer (PCa). However, the majority of PCa patients receiving the androgen deprivation therapy develop recurrent castration-resistant prostate cancer (CRPC) within two years. Chemotherapies show little effect on prolonging survival of CRPC patients and new treatments are needed. Previous studies reported that the extracts from rooibos (Aspalathus linearis) exhibit chemopreventive properties in some cancer models, including skin, liver and oesophagus cancers in animals. We therefore investigate if extracts from rooibos can suppress the proliferation of CRPC cells. PURPOSE: We investigated whether an aspalathin-rich green rooibos extract (GRT™; 12.78 g aspalathin/100 g extract) demonstrates anti-cancer activity against CRPC cells. METHODS: High performance liquid chromatography (HPLC) was used to profile the major flavonoids in GRT. Hoechst-dye proliferation assay, 3,4,5-dimethylthiazol-2-yl)-2-5-diphenyltetrazolium bromide (MTT) viability assay and flow cytometry assay were used to explore the effects of GRT on the proliferation and cell cycle progression of CRPC cells. Comet assay was used to survey whether GRT induces apoptosis in CRPC cells. LNCaP 104-R1 xenograft nude mice model was used to determine the inhibitory effect of GRT on CRPC tumors in vivo. Micro-Western Array (MWA) and Western blot analysis were carried out to unravel the underlying molecular mechanism. RESULTS: GRT contained aspalathin as the most abundant flavonoid. GRT suppressed the proliferation and survival of LNCaP 104-R1, LNCaP FGC and PC-3 PCa cells. Flow cytometry analysis showed that GRT decreased the population of PCa cells in S phase but increased the cell population in G2/M phase. Comet assay confirmed that GRT induced apoptosis in LNCaP 104-R1 cells. Gavage of 400 mg/kg GRT suppressed LNCaP 104-R1 xenografts in castrated nude mice. MWA and Western blot analysis indicated that GRT treatment suppressed Akt1, phospho-Akt Ser473, Cdc2, Bcl-2, TRAF4 and Aven, but increased activated Caspase 3, cytochrome c, and p27Kip1. Overexpression of Akt rescued the suppressive effects of GRT on CRPC cells. Co-treatment of GRT with Bcl-2 inhibitor ABT-737, PI3K inhibitor LY294002 and Akt inhibitor GSK 690693 exhibited additive inhibitory effect on proliferation of CRPC cells. CONCLUSIONS: GRT suppresses the proliferation of CRPC cells via inhibition of Akt signaling. SN - 1618-095X UR - https://www.unboundmedicine.com/medline/citation/31419729/Rooibos_suppresses_proliferation_of_castration-resistant_prostate_cancer_cells_via_inhibition_of_Akt_signaling L2 - https://linkinghub.elsevier.com/retrieve/pii/S0944-7113(19)30233-8 DB - PRIME DP - Unbound Medicine ER -