RESUMO
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.
Assuntos
Antineoplásicos/farmacologia , Neoplasias Experimentais/tratamento farmacológico , Fenilpropionatos/farmacologia , Própole/farmacologia , Quinases Ativadas por p21/metabolismo , Animais , Ácidos Cafeicos/farmacologia , Linhagem Celular Tumoral , Feminino , Camundongos , Camundongos Nus , Neurofibromatoses/tratamento farmacológico , Álcool Feniletílico/análogos & derivados , Álcool Feniletílico/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Artepillin C is the major compound in the Brazilian green propolis from Baccharis dracunculifolia. Our aim in this study was to investigate the anti-inflammatory effects, absorption, and bioavailability of Artepillin C in mice. The animals used were male Swiss mice subjected to: paw oedema by carrageenan (300 microg/paw), carrageenan-induced peritonitis, and prostaglandin E(2) determination. We also measured in vitro nitric oxide production by RAW 264.7 cells and NF-kappaB activity in HEK 293 cells. Finally, we measured the absorption and bioavailability of Artepillin C in plasma from mice by means of GC-MS after a single oral dose (10 mg/kg). In vivo, Artepillin C produced a maximal inhibition of 38% after 360 min on paw oedema. Artepillin C also decreased the number of neutrophils during peritonitis (IC(50): 0.9 (0.5-1.4) mg/kg). Treatment with Artepillin C decreased prostaglandin E(2) by 29+/-3% and 58+/-5% at 1 and 10 mg/kg, respectively, with a mean ID(50) of 8.5 (8.0-8.7) mg/kg). Similarly, in in vitro models, Artepillin C (3, 10, or 100 microM) decreased nitric oxide production by RAW 264.7 cells with a mean IC(50) of 8.5 (7.8-9.2) microM. In HEK 293 cells, Artepillin C reduced NF-kappaB activity with a mean IC(50) of 26 (22-30) mug/ml), suggesting anti-inflammatory activity, particularly during acute inflammation. Lastly, Artepillin C was absorbed after an oral dose (10 mg/kg) with maximal peaks found at 1 h (22 microg/ml). Collectively, Artepillin C showed anti-inflammatory effects mediated, at least in part, by prostaglandin E(2) and nitric oxide inhibition through NF-kappaB modulation, and exhibited bioavailability by oral administration.
Assuntos
Anti-Inflamatórios , Fenilpropionatos/farmacologia , Própole/química , Animais , Disponibilidade Biológica , Carragenina , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Dinoprostona/metabolismo , Edema/induzido quimicamente , Edema/prevenção & controle , Indicadores e Reagentes , Indometacina/farmacologia , Absorção Intestinal , Leupeptinas/farmacologia , Masculino , Camundongos , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Nitritos/metabolismo , Fenilpropionatos/química , Fenilpropionatos/farmacocinética , Ativação TranscricionalRESUMO
Propolis, a resinous substance collected by honeybees from various plant sources, possesses various physiological activities such as antitumor effects. We have previously shown that propolis of Brazilian origin was composed mainly of artepillin C and that its constituents were quite different from those of propolis of European origin. In this report, we examined an antiangiogenic effects of Brazilian propolis and investigated whether artepillin C was responsible for such effects. In an in vivo angiogenesis assay using ICR mice, we found that the ethanol extract of Brazilian propolis (EEBP) significantly reduced the number of newly formed vessels. EEBP also showed antiangiogenic effects in an in vitro tube formation assay. When compared with other constituents of EEBP, only artepillin C was found to significantly inhibit the tube formation of HUVECs in a concentration-dependent manner (3.13-50microg/ml). In addition, artepillin C significantly suppressed the proliferation of HUVECs in a concentration-dependent manner (3.13-50microg/ml). Furthermore, artepillin C significantly reduced the number of newly formed vessels in an in vivo angiogenesis assay. Judging from its antiangiogenic activity in vitro and in vivo, we concluded that artepillin C at least in part is responsible for the antiangiogenic activity of EEBP in vivo. Artepillin C may prove useful in the development of agents and foods with therapeutic or preventive activity against tumor angiogenesis.
Assuntos
Proliferação de Células/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Neoplasias/irrigação sanguínea , Neovascularização Patológica/prevenção & controle , Fenilpropionatos/farmacologia , Própole/química , Animais , Brasil , Células Cultivadas , Endotélio Vascular/citologia , Humanos , CamundongosRESUMO
Hydrogen transfer from artepillin C to cumylperoxyl radical proceeds via one-step hydrogen atom transfer rather than via electron transfer, the rate constant of which is comparable to that of (+)-catechin, indicating that artepillin C can act as an efficient antioxidant.
Assuntos
Fenilpropionatos/química , Fenilpropionatos/farmacologia , Própole/química , Catequina/química , Sequestradores de Radicais Livres/química , Sequestradores de Radicais Livres/farmacologia , Radicais Livres/antagonistas & inibidores , Radicais Livres/química , Hidrogênio/química , Cinética , Inibidores da Síntese de Ácido Nucleico , Peróxidos/antagonistas & inibidores , Peróxidos/químicaRESUMO
We have demonstrated that prenylation of p-halophenols was dependent on the solvent effect and succeeded in o,o'-diprenylation of p-halophenols in water. Following the Mizoroki-Heck coupling of the diprenyl-p-iodophenol 3c with methyl acrylate and then hydrolysis, we first synthesized artepillin C [3-(4-hydroxy-3,5-di(3-methyl-2-butenyl)phenyl)-2(E)-propenoic acid] (1), which is a biologically active constituent of propolis. These reactions may be applicable to the synthesis of various useful natural products such as 2,4,6-trisubstituted phenol derivatives.