RESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Furanodiene is an active ingredient of the traditional Chinese medicine, Rhizoma Curcumae, commonly used for the treatment of cancer in China. AIM OF THE STUDY: To investigate the anti-cancer property of Rhizoma Curcumae, this study describes the anti-angiogenic activities of furanodiene in human umbilical vein endothelial cells (HUVECs) in vitro and in zebrafish in vivo. MATERIALS AND METHODS: HUVECs were treated with different doses of furanodiene in the presence or absence of vascular endothelial growth factor (VEGF). The anti-proliferative effect of furanodiene was measured using the XTT assay. The anti-migration and anti-invasion activities of this compound were investigated with a wound-healing migration model and a three-dimensional cell invasion model, respectively. The effects of furanodiene on HUVEC differentiation were assessed by in vitro tube formation in Matrigel™. The expression of related proteins was detected by Western blot. Morphological observations of zebrafish were evaluated in transgenic Tg (fli1: EGFP) zebrafish embryos. RESULTS: Our results showed that furanodiene exposure could significantly inhibit the proliferation of HUVECs in a dose-dependent manner and inhibit VEGF-induced proliferation at a low dose. Relative to the VEGF-induced control, the number of invading and migrating cells was significantly reduced in the furanodiene-treated groups. Furanodiene also dramatically suppressed tube formation and p-Akt (Ser473), p-Erk 1/2 (Thr202/Tyr204), ICAM-1, p-p85 (Ser428) as well as p85 protein expression. Furthermore, exposure to furanodiene inhibited angiogenesis in the zebrafish model. CONCLUSIONS: This study demonstrated that furanodiene exposure exhibits a potential anti-angiogenic effect through suppression of endothelial cell growth, invasion, migration and tube formation via regulation of the PI3K pathway. This potential anti-angiogenic effect of furanodiene may play an important role in the anti-tumor activity of the traditional Chinese medicine, Rhizoma Curcumae.
Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Curcuma , Medicamentos de Ervas Chinesas/farmacologia , Furanos/farmacologia , Compostos Heterocíclicos com 2 Anéis/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Neovascularização Fisiológica/efeitos dos fármacos , Inibidores da Angiogênese/isolamento & purificação , Animais , Animais Geneticamente Modificados , Antineoplásicos Fitogênicos/isolamento & purificação , Western Blotting , Diferenciação Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Classe Ia de Fosfatidilinositol 3-Quinase/metabolismo , Curcuma/química , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/isolamento & purificação , Furanos/isolamento & purificação , Proteínas de Fluorescência Verde/biossíntese , Proteínas de Fluorescência Verde/genética , Compostos Heterocíclicos com 2 Anéis/isolamento & purificação , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Medicina Tradicional Chinesa , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fosforilação , Plantas Medicinais , Proteína Proto-Oncogênica c-fli-1/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina , Transdução de Sinais/efeitos dos fármacos , Treonina , Tirosina , Fator A de Crescimento do Endotélio Vascular/metabolismo , Cicatrização/efeitos dos fármacos , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Peixe-Zebra/metabolismoRESUMO
Ganoderic acid DM (GADM) is a triterpenoid isolated from Ganoderma lucidum, a well-known edible medicinal mushroom. In the present study, we found that GADM effectively inhibited cell proliferation and colony formation in MCF-7 human breast cancer cells, which was much stronger than that of MDA-MB-231 breast cancer cells. GADM both concentration- and time-dependently mediated G1 cell cycle arrest and significantly decreased the protein level of CDK2, CDK6, cycle D1, p-Rb and c-Myc in MCF-7 cells. Moreover, GADM obviously induced DNA fragmentation and cleavage of PARP which are the characteristics of apoptosis and decreased the mitochondrial membrane potential in MCF-7 cells. Besides, we also showed that GADM elicited DNA damage as measured by comet assay which is a sensitive method for DNA damage detection. γ-H2AX, a marker of DNA damage, was also slightly up-regulated after treated with GADM for 6h, suggesting that the G1 cell cycle arrest and apoptosis induced by GADM may be partially resulted from GADM-induced DNA damage. These results have advanced our current understandings of the anti-cancer mechanisms of GADM.