Caffeic acid phenethyl ester suppresses EGFR/FAK/Akt signaling, migration, and tumor growth of prostate cancer cells.

BACKGROUND: Epidermal growth factor receptor (EGFR) is upregulated in prostate cancer (PCa). However, suppression of EGFR did not improve the patient outcome, possibly due to the activation of PI3K/Akt signaling in PCa. Compounds able to suppress both PI3K/Akt and EGFR signaling may be effective for treating advanced PCa. PURPOSE: We examined if caffeic acid phenethyl ester (CAPE) simultaneously suppresses the EGFR and Akt signaling, migration and tumor growth in PCa cells. METHODS: Wound healing assay, transwell migration assay and xenograft mice model were used to determine the effects of CAPE on migration and proliferation of PCa cells. Western blot, immunoprecipitation, and immunohistochemistry staining were performed to determine the effects of CAPE on EGFR and Akt signaling. RESULTS: CAPE treatment decreased the gene expression of HRAS, RAF1, AKT2, GSK3A, and EGF and the protein expression of phospho-EGFR (Y845, Y1069, Y1148, Y1173), phospho-FAK, Akt, and ERK1/2 in PCa cells. CAPE treatment inhibited the EGF-induced migration of PCa cells. Combined treatment of CAPE with EGFR inhibitor gefitinib showed additive inhibition on migration and proliferation of PCa cells. Injection of CAPE (15 mg/kg/3 days) for 14 days suppressed the tumor growth of prostate xenografts in nude mice as well as suppressed the levels of Ki67, phospho-EGFR Y845, MMP-9, phospho-Akt S473, phospho-Akt T308, Ras, and Raf-1 in prostate xenografts. CONCLUSIONS: Our study suggested that CAPE can simultaneously suppress the EGFR and Akt signaling in PCa cells and is a potential therapeutic agent for advanced PCa.

Rooibos suppresses proliferation of castration-resistant prostate cancer cells via inhibition of Akt signaling.

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.

Caffeic acid phenethyl ester suppresses proliferation and survival of TW2.6 human oral cancer cells via inhibition of Akt signaling.

Caffeic acid phenethyl ester (CAPE) is a bioactive component extracted from honeybee hive propolis. Our observations indicated that CAPE treatment suppressed cell proliferation and colony formation of TW2.6 human oral squamous cell carcinoma (OSCC) cells dose-dependently. CAPE treatment decreased G1 phase cell population, increased G2/M phase cell population, and induced apoptosis in TW2.6 cells. Treatment with CAPE decreased protein abundance of Akt, Akt1, Akt2, Akt3, phospho-Akt Ser473, phospho-Akt Thr 308, GSK3ß, FOXO1, FOXO3a, phospho-FOXO1 Thr24, phospho-FoxO3a Thr32, NF-κB, phospho-NF-κB Ser536, Rb, phospho-Rb Ser807/811, Skp2, and cyclin D1, but increased cell cycle inhibitor p27Kip. Overexpression of Akt1 or Akt2 in TW2.6 cells rescued growth inhibition caused by CAPE treatment. Co-treating TW2.6 cells with CAPE and 5-fluorouracil, a commonly used chemotherapeutic drug for oral cancers, exhibited additive cell proliferation inhibition. Our study suggested that administration of CAPE is a potential adjuvant therapy for patients with OSCC oral cancer.

Caffeic Acid phenethyl ester as a potential treatment for advanced prostate cancer targeting akt signaling.

Prostate cancer is the fifth most common cancer overall in the world. Androgen ablation therapy is the primary treatment for metastatic prostate cancer. However, most prostate cancer patients receiving the androgen ablation therapy ultimately develop recurrent castration-resistant tumors within 1-3 years after treatment. The median overall survival time is 1-2 years after tumor relapse. Chemotherapy shows little effect on prolonging survival for patients with metastatic hormone-refractory prostate cancer. More than 80% of prostate tumors acquire mutation or deletion of tumor suppressor phosphatase and tensin homolog (PTEN), a negative regulator of PI3K/Akt signaling, indicating that inhibition of PI3K/Akt might be a potential therapy for advanced prostate tumors. Caffeic acid phenethyl ester (CAPE) is a strong antioxidant extracted from honeybee hive propolis. CAPE is a well-known NF-κB inhibitor. CAPE has been used in folk medicine as a potent anti-inflammatory agent. Recent studies indicate that CAPE treatment suppresses tumor growth and Akt signaling in human prostate cancer cells. We discuss the potential of using CAPE as a treatment for patients with advanced prostate cancer targeting Akt signaling pathway in this review article.

Anti-oxidative and anti-inflammatory activities of two different species of a Chinese herb I-Tiao-Gung.

The anti-oxidative and anti-inflammatory activities of two different species of traditional Chinese medicines that shared the same name have been studied. The extracts of Glycine radix have higher activities in free radical-scavenging activity determined with DPPH, reduction in hemoglobin-catalyzed lipid auto-oxidation and inhibition of the lipoxygenase (LOX) and cyclooxygenase (COX)-catalyzed arachidonate oxidation compared to the activities of extract of Flemingia. One of the significant bioactive constituents of Glycine radix has been isolated and identified as daidzein.