RESUMO
αglucosidase is a key enzyme that plays a role in glucose absorption in the gastrointestinal tract, and the inhibition of its activity induces the prevention of postprandial hyperglycemia. Several αglucosidase inhibitors have been used as medicines for type 2 diabetes, but a similar effect is observed in natural resources, including traditional herbs and their phytochemicals. To identify the presence of the αglucosidase inhibitory activity in herbs, in which various functional effects have been known to occur, the present study investigated the effects of hotwater extracts of 26 types of herbs on αglucosidase activity in an in vitro assay. The results indicated significant increases in the inhibition of αglucosidase activity in 1,000 µg/ml olive (P<0.01), white willow (P<0.01) and red rooibos hotwater extracts. Furthermore, ≥50% inhibition of αglucosidase activity was determined to be significant in 1,000 µg/ml coltsfoot, green tea and bearberry hotwater extracts. In addition, the effects of bearberry, green tea and coltsfoot hotwater extracts on αglucosidase activity in vivo were evaluated according to the blood glucose levels (BGLs) in maltose and glucose load model rats. It was indicated that the administration of these three herb extracts significantly reduced the increasing BGLs after maltose loading until 0.5 h compared with the control group. However, only coltsfoot extract significantly reduced the increasing BGLs after glucose loading until 0.5 h compared with the control group. Thus, the present results may facilitate the understanding of a novel functionality in traditional herbs, which could be useful for the prevention of disease onset and progression, such as in hyperglycemia and type 2 diabetes.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores de Glicosídeo Hidrolases/administração & dosagem , Plantas Medicinais/química , Água/administração & dosagem , alfa-Glucosidases/metabolismo , Animais , Arctostaphylos/química , Aspalathus/química , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/enzimologia , Modelos Animais de Doenças , Glucose/efeitos adversos , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Temperatura Alta , Masculino , Maltose/efeitos adversos , Olea/química , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Ratos , Salix/química , Chá/química , Tussilago/química , Água/química , Água/farmacologiaRESUMO
Cancer is a diverse class of diseases characterized by uncontrolled cell growth with the potential to invade and spread to other parts of the body, and continues to be one of the leading causes of death worldwide. Conventional cancer treatment modalities include antitumor drugs, surgical resection, locally targeted therapies such as radiation therapy. Along with improved understanding of the molecular pathogenesis of various cancers, generation and the use of smart targeted anti-cancer drugs have been challenged. The need for novel therapeutic strategies remains paramount given the sustained development of drug resistance, tumor recurrence, and metastasis. Development of new strategies aimed at improving chemotherapy sensitivity and minimizing the adverse side effects is thus essential for obtaining satisfied therapeutic outcomes for patients and enhancing their quality of life. Emerging evidence has reported that many cancer patients use either herbs employed in complementary therapies or dietary agents that influence cellular signaling worldwide. Numerous components of edible plants, collectively termed phytochemicals that have beneficial effects for health, are being reported increasingly in the scientific literature. Of those, flavonoids have attracted much attention by virtue of its wide variety of biological functions including antioxidant, anti-inflammatory, and anticancer activity. In this review, we highlight the molecular mechanisms underlying its multiple pharmacological effects, especially focusing on cancer chemoprevention. We further discuss possible strategies to develop anticancer therapy by combining flavonoids nutraceuticals and conventional chemotherapeutic agents. We also highlight numerous pharmacokinetic challenges such as bioavailability, drug-drug interactions, which are still fundamental questions concerning its future clinical application.
RESUMO
We have demonstrated that an extract from the ripe fruit of Vitex angus-castus (Vitex), might be a promising anticancer candidate. In order to further provide a molecular rationale for clinical development in anticancer therapy, a detailed mechanism underlying the efficacy of Vitex against HL-60 cells was investigated. Vitex induced a dose- and time-dependent decrease in cell viability associated with induction of apoptosis and G(2)/M cell cycle arrest, both of which were suppressed by the addition of SB203580, an inhibitor for p38 MAPK. Furthermore, SB203580 significantly suppressed Vitex-induced phosphorylation of histone H3, a downstream molecule of p38 MAPK known to be involved in apoptosis induction in tumor cells. Notably, Vitex induced upregulation of intracellular ATP, known to bind its binding pocket inside activated p38 MAPK and to be required for the activation of p38 MAPK pathway. These results, thus, suggest that upregulation of intracellular ATP and phosphorylation of histone H3 are closely associated with the activation of p38 MAPK pathway, consequently contributing to Vitex-mediated cytotoxicity. Intriguingly, a significant decrease of intracellular ROS levels and downregulation of expression level of gp91(phox), an important component of NADPH oxidase, were observed in Vitex-treated cells. A greater decline in ROS levels along with enhanced apoptosis was observed after treatment with Vitex in combination with SnPP, an inhibitor specific for HO-1. Since NADPH oxidase and HO-1 are closely correlated to redox status associated with intracellular ROS levels, the two enzymes are suggested to be implicated in Vitex-mediated cytotoxicity in HL-60 cells by regulating ROS generation. We also suggest that activation of the p38 MAPK pathway may be dependent on the alterations of intracellular ATP levels, rather than that of intracellular ROS levels. These results may have important implications for appropriate clinical uses of Vitex and provide novel insights into the interaction between Vitex and other conventional drugs capable of affecting intracellular redox status.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Histonas/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Vitex/química , Apoptose/efeitos dos fármacos , Western Blotting , Sobrevivência Celular/efeitos dos fármacos , Fragmentação do DNA , Frutas , Células HL-60 , Humanos , Fosforilação/efeitos dos fármacos , Fitoterapia/métodos , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
We have demonstrated that an extract from the ripe fruit of Vitex agnus-castus (Vitex) exhibits cytotoxic activities against various types of solid tumor cells, whereas its effects on leukemia cells has not been evaluated to date. In this study, the effects of Vitex and its major component, casticin, on leukemia cell lines, HL-60 and U-937, were investigated by focusing on proliferation, induction of apoptosis and differentiation. Identification and quantitation by NMR spectroscopy showed that casticin accounted for approximate 1% weight of Vitex. Dose-dependent cytotoxicity of Vitex and casticin was observed in both cell lines, and HL-60 cells were more sensitive to the cytotoxicity of Vitex/casticin compared to U-937 cells. Furthermore, compared to unstimulated HL-60 cells, phorbol 12-myristate 13-acetate (PMA)- and 1,25-dihydroxyvitamin D3 (VD3)-differentiated HL-60 cells acquired resistance to Vitex/casticin based on the results from cell viability and apoptosis induction analysis. Since the HL-60 cell line is more immature than the U-937 cell line, these results suggested that the levels of cytotoxicity of Vitex/casticin were largely attributed to the degree of differentiation of leukemia cells; that is, cell lines with less differentiated phenotype were more susceptible than the differentiated ones. RT-PCR analysis demonstrated that PMA upregulated the expression of intercellular adhesion molecule-1 (ICAM-1) in HL-60 cells, and that anti-ICAM-1 monoclonal antibody not only abrogated PMA-induced aggregation and adhesion of the cells but also restored its sensitivity to Vitex. These results suggested that ICAM-1 plays a crucial role in the acquired resistance in PMA-differentiated HL-60 cells by contributing to cell adhesion. These findings provide fundamental insights into the clinical application of Vitex/casticin for hematopoietic malignancy.
Assuntos
Diferenciação Celular/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Flavonoides/farmacologia , Leucemia/tratamento farmacológico , Adulto , Apoptose/efeitos dos fármacos , Calcitriol/farmacologia , Agonistas dos Canais de Cálcio/farmacologia , Carcinógenos/farmacologia , Adesão Celular/fisiologia , Diferenciação Celular/fisiologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Células HL-60 , Humanos , Molécula 1 de Adesão Intercelular/biossíntese , Extratos Vegetais/farmacologia , Acetato de Tetradecanoilforbol/farmacologia , VitexRESUMO
The proliferation of a human colon carcinoma cell line, COLO 201, was effectively suppressed through apoptosis in the presence of flavonoids, an ethanol extract from Vitex agnus-castus fruits. The induction of apoptosis was not inhibited by the presence of an anti-oxidant, N-acetyl-L-cysteine, whereas only HO-1 gene expression levels increased among other typical oxidative stress-associated genes examined after Vitex treatment. These results suggest that Vitex treatment activates a pathway associated with HO-1 gene activation, resulting in the induction of apoptosis in COLO 201. Results also implicate a potential clinical chemotherapeutic application of Vitex for the treatment of colon cancer patients.