Artepillin C (3,5-diprenyl-4-hydroxycinnamic acid) sensitizes LNCaP prostate cancer cells to TRAIL-induced apoptosis.
ABSTRACT Naturally occurring phenolic compounds have been shown to sensitize prostate cancer cells to tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. TRAIL is a potent stimulator of apoptosis in cancer cells and an important immune effector molecule in the surveillance and elimination of developing tumours. However, many cancer cells are resistant to TRAIL-mediated death. In this study, we aimed to determine the mechanisms by which TRAIL resistance can be overcome in prostate cancer cells by 3,5-diprenyl-4-hydroxycinnamic acid (artepillin C). Artepillin C is a bioactive component of Brazilian green propolis that possesses antitumour and chemopreventive activities. TRAIL-resistant LNCaP prostate cancer cells were treated with TRAIL and artepillin C. Cytotoxicity was measured by MTT and lactate dehydrogenase (LDH) assays. Apoptosis was detected using Annexin V-FITC staining by flow cytometry and fluorescence microscopy. Death receptor (DR) (TRAIL-R1/DR4 and TRAIL-R2/DR5) expression was analyzed using flow cytometry. Mitochondrial membrane potential (∆ψm) was evaluated using DePsipher staining by fluorescence micro-scopy. The inhibition of NF-κB (p65) activation was confirmed with the ELISA-based TransAM NF-κB kit. Caspase-8 and caspase-3 activities were determined by colorimetric protease assays. The results showed that artepillin C sensitized the TRAIL-resistant LNCaP cells by engaging the extrinsic (receptor-mediated) and intrinsic (mitochondrial) apoptotic pathways. Artepillin C increased the expression of TRAIL-R2 and decreased the activity of NF-κB. Co-treatment with TRAIL and artepillin C induced the significant activation of caspase-8 and caspase-3, as well as the disruption of ∆ψm. These findings show that prostate cancer cells can be sensitized to TRAIL-mediated immunoprevention by artepillin C and confirm the role of phenolic compounds in prostate cancer immunochemoprevention.
- SourceAvailable from: Wojciech Król[show abstract] [hide abstract]
ABSTRACT: Prostate cancer is a commonly diagnosed cancer in men. The ethanolic extract of propolis (EEP) and its phenolic compounds possess immunomodulatory, chemopreventive and antitumor effects. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/APO2L) is a naturally occurring anticancer agent that preferentially induces apoptosis in cancer cells and is not toxic to normal cells. We examined the cytotoxic and apoptotic effects of EEP and phenolic compounds isolated from propolis in combination with TRAIL on two prostate cancer cell lines, hormone-sensitivity LNCaP and hormone-refractory DU145. The cytotoxicity was evaluated by MTT and LDH assays. The apoptosis was determined using flow cytometry with annexin V-FITC/propidium iodide. The prostate cancer cell lines were proved to be resistant to TRAIL-induced apoptosis. Our study demonstrated that EEP and its components significantly sensitize to TRAIL-induced death in prostate cancer cells. The percentage of the apoptotic cells after cotreatment with 50 μg mL(-1) EEP and 100 ng mL(-1) TRAIL increased to 74.9 ± 0.7% for LNCaP and 57.4 ± 0.7% for DU145 cells. The strongest cytotoxic effect on LNCaP cells was exhibited by apigenin, kaempferid, galangin and caffeic acid phenylethyl ester (CAPE) in combination with TRAIL (53.51 ± 0.68-66.06 ± 0.62% death cells). In this work, we showed that EEP markedly augmented TRAIL-mediated apoptosis in prostate cancer cells and suggested the significant role of propolis in chemoprevention of prostate cancer.Evidence-based Complementary and Alternative Medicine 11/2009; 2011:535172. · 1.72 Impact Factor
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ABSTRACT: Kaempferol is a natural compound contained in edible plants, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anti-cancer agent. Here, we show for the first time that the combined treatment with kaempferol and TRAIL drastically induced apoptosis in human colon cancer SW480 cells, compared to single treatments. Kaempferol markedly up-regulated TRAIL receptors, DR5 and DR4. DR5 but not DR4 siRNA efficiently blocked apoptosis induced by the co-treatment with kaempferol and TRAIL, indicating that DR5 up-regulation by kaempferol helps to enhance TRAIL actions. Moreover, we examined the combined effect on normal human cells. The co-treatment induced no apoptosis in normal human peripheral blood mononuclear cells and little apoptosis in normal human hepatocytes. These results suggest that kaempferol is useful for TRAIL-based treatments for cancer.Biochemical and Biophysical Research Communications 11/2008; 375(1):129-33. · 2.41 Impact Factor
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ABSTRACT: There are mainly three types of propolis whose major anticancer ingredients are entirely different: (1) CAPE (caffeic acid phenethyl ester)-based propolis in Europe, Far East and New Zealand, (2) artepillin C (ARC)-based Brazilian green propolis and (3) Brazilian red propolis. It was shown previously that NF (neurofibromatosis)-associated tumors require the kinase PAK1 for their growth, and CAPE-based propolis extracts such as Bio 30 suppress completely the growth of NF tumors in vivo by blocking PAK1 signaling. Also it was demonstrated that ARC suppresses angiogenesis, suggesting the possibility that ARC also blocks oncogenic PAK1 signaling. Here it is shown for the first time that both ARC and green propolis extract (GPE) indeed block the PAK1 signaling selectively, without affecting another kinase known as AKT. Furthermore, it was confirmed that ARC as well as GPE suppress almost completely the growth of human NF tumor xenografts in mice, as does Bio 30. These results suggest that both CAPE-based and ARC-based propolis extracts are natural anti-PAK1 remedies and could be among the first effective NF therapeutics available on the market. Since more than 70% of human cancers such as breast and prostate cancers require the kinase PAK1 for their growth, it is quite possible that GPE could be potentially useful for the treatment of these cancers, as is Bio 30.Phytotherapy Research 11/2008; 23(3):423-7. · 2.07 Impact Factor