RESUMO
BACKGROUND: Previous studies have shown a major green tea polyphenol (-)-epigallocatechin-3-gallate ((-)-EGCG) as a powerful anti-cancer agent. However, its poor bioavailability and requirement of a high dosage to manifest activity have restricted its clinical application. Recently, our team synthesized a peracetate-protected derivative of EGCG, which can act as a prodrug of (-)-EGCG (ProEGCG) with enhanced stability and improved bioavailability in vitro and in vivo. Herein, we tested the therapeutic efficacy of this novel ProEGCG, in comparison to EGCG, toward human endometrial cancer (EC). METHODS: In this study, the effects of ProEGCG and EGCG treatments on cell growth, cell survival and modulation of intracellular signaling pathways in RL95-2 and AN3 CA EC cells were compared. The antiproliferative effect was evaluated by cell viability assay. Apoptosis was measured by annexin/propidium iodide staining. Expression of mitogen-activated protein kinases, markers of proliferation and apoptosis were measured by immunoblot analysis. In addition, the effects of ProEGCG and EGCG on tumor growth, vessel formation and gene expression profiles on xenograft models of the EC cells were investigated. RESULTS: We found that treatment with ProEGCG, but not EGCG, inhibited, in a time- and dose-dependent manner, the proliferation and increased apoptosis of EC cells. Treatment with low-dose ProEGCG significantly enhanced phosphorylation of JNK and p38 MAPK and inhibited phosphorylation of Akt and ERK which are critical mediators of apoptosis. ProEGCG, but not EGCG, elicited a significant decrease in the growth of the EC xenografts, promoted apoptotic activity of tumour cells in the EC xenografts, and decreased microvessel formation, by differentially suppressing anti-apoptotic molecules, NOD1 and NAIP. Notably, no obvious adverse effects were detected. CONCLUSIONS: Taken together, ProEGCG at a low dose exhibited anticancer activity in EC cells through its anti-proliferative, pro-apoptotic and anti-tumor actions on endometrial cancer in vitro and in vivo. In contrast, a low dose of EGCG did not bring about similar effects. Importantly, our data demonstrated the efficacy and safety of ProEGCG which manifests the potential of a novel anticancer agent for the management of endometrial cancer.
Assuntos
Catequina/análogos & derivados , Neoplasias do Endométrio/tratamento farmacológico , Pró-Fármacos/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Chá/química , Animais , Apoptose , Catequina/química , Proliferação de Células , Feminino , Humanos , Camundongos , Camundongos Nus , Pró-Fármacos/farmacologia , Transdução de SinaisRESUMO
This article reviews mushrooms with anti-breast cancer activity. The mushrooms covered which are better known include the following: button mushroom Agaricus bisporus, Brazilian mushroom Agaricus blazei, Amauroderma rugosum, stout camphor fungus Antrodia camphorata, Jew's ear (black) fungus or black wood ear fungus Auricularia auricula-judae, reishi mushroom or Lingzhi Ganoderma lucidum, Ganoderma sinense, maitake mushroom or sheep's head mushroom Grifola frondosa, lion's mane mushroom or monkey head mushroom Hericium erinaceum, brown beech mushroom Hypsizigus marmoreus, sulfur polypore mushroom Laetiporus sulphureus, Lentinula edodes (shiitake mushroom), Phellinus linteus (Japanese "meshimakobu," Chinese "song gen," Korean "sanghwang," American "black hoof mushroom"), abalone mushroom Pleurotus abalonus, king oyster mushroom Pleurotus eryngii, oyster mushroom Pleurotus ostreatus, tuckahoe or Fu Ling Poria cocos, and split gill mushroom Schizophyllum commune. Antineoplastic effectiveness in human clinical trials and mechanism of anticancer action have been reported for Antrodia camphorata, Cordyceps sinensis, Coriolus versicolor, Ganoderma lucidum, Grifola frondosa, and Lentinula edodes.
Assuntos
Agaricales/química , Agaricales/classificação , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Ensaios Clínicos como Assunto , Misturas Complexas/química , Misturas Complexas/farmacologia , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , RatosRESUMO
Fatty liver (FLD) disease is a consequence of metabolic syndrome, which is a health problem worldwide with a phenomenal rise in prevalence. In this study, two hepatoprotective polysaccharide-peptides were extracted from the mushroom Auricularia polytricha followed by chromatographic fractionation of the extract on the ion exchanger DEAE-cellulose and gel filtration on Sephadex-200 to yield two purified fractions: APPI and APPII. The monosaccharide compositions, FT-IR, N-terminal sequences, internal peptide sequences and molecular weights of the two fractions were determined. Furthermore, their hepatoprotective effect on human hepatoma HepG2 cells in vitro and in an animal model of fatty liver disease was evidenced by the findings that APPI and APPII diminished lipid deposit in cells, blood and the liver, increased cellular antioxidant activity and viability, and protected the liver against injury. The mechanistic study revealed that APPI and APPII activated the adiponectin pathway, up-regulated expression of genes controlling free fatty acid (FFA) oxidation, such as AMPK, CPTl, ACOX1 and PPARα genes, enhanced lipid metabolism, preserved hepatic function, promoted the antioxidant defense system and reduced lipid peroxidation. Hence the bioactive compounds of A. polytricha could serve as therapeutic agents in the food and pharmaceutical industries.
Assuntos
Agaricales , Produtos Biológicos/uso terapêutico , Fígado Gorduroso/tratamento farmacológico , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Substâncias Protetoras/uso terapêutico , Animais , Produtos Biológicos/farmacologia , Modelos Animais de Doenças , Ácidos Graxos não Esterificados/metabolismo , Fígado Gorduroso/metabolismo , Células Hep G2 , Humanos , Fígado/metabolismo , Masculino , Substâncias Protetoras/farmacologia , Ratos , Ratos WistarRESUMO
The genus Panax consists of a group of prized medicinal herbs. Major members of the Panax genus include P. ginseng, P. notoginseng, P. quinquefolius, and P. vietnamensis. They possess various bioactive constituents such as ginsenosides, saponins, polysaccharides and proteins. Many of them were reported to show beneficial effects on human health. Ginsenosides and saponins of ginsengs caught the sight of most researchers. Precise investigations revealed their roles on improvement of the functioning of the nervous system, cardiovascular system, and other functions. In contrast, our knowledge of the bioactive Panax proteins is relatively limited. A number of proteins from P. ginseng, the most valuable member of Panax species, have been investigated and proved to be beneficial to our body. Meanwhile, a few bioactive P. notoginseng proteins, such as ribonucleases and antifungal proteins, have been characterized and reported. We summarize herein the proteins present in P. notoginseng that have been identified, and try to compare them with those from other Panax species with a similar structure or bioactivity, and conclude whether the proteins in P. notoginseng have any distinctive features.
Assuntos
Panax notoginseng/química , Proteínas de Plantas , Raízes de Plantas/química , Animais , Humanos , Proteínas de Plantas/química , Proteínas de Plantas/metabolismo , Proteínas de Plantas/farmacologiaRESUMO
Lectins are proteins or glycoproteins of non-immune origin which have at least one noncatalytic domain that bind reversibly to specific mono or oligosaccharides. Traditional Chinese Medicine (TCM) involves a broad range of medicinal practices sharing common concepts which have been developed in China and are based on a tradition of more than thousands of years. Plant materials which are commonly used in TCM as a complementary or alternative for Western medical treatments contain a considerable number of important lectins. These lectins have been reported to have various applications and uses such as cancer treatment, glycoconjugate research, biomarker development, and others. Here, we summarize the available literature related to lectins from TCM and recent trends in their potential biomedical applications.
Assuntos
Lectinas , Medicina Tradicional Chinesa , Animais , Glicoproteínas/isolamento & purificação , Glicoproteínas/uso terapêutico , Humanos , Lectinas/isolamento & purificação , Lectinas/uso terapêutico , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/uso terapêuticoRESUMO
A variety of fungi, plants, and their different tissues are used in Traditional Chinese Medicine to improve health, and some of them are recommended for dietary therapy. Many of these plants and fungi contain antifungal proteins and peptides which suppress spore germination and hyphal growth in phytopathogenic fungi. The aim of this article is to review antifungal proteins produced by medicinal plants and fungi used in Chinese medicine which also possess anticancer and human immunodeficiency virus-1 (HIV-1) enzyme inhibitory activities.
Assuntos
Fármacos Anti-HIV/farmacologia , Antifúngicos , Antineoplásicos , Proteínas Fúngicas , Proteínas de Plantas , Plantas Medicinais/química , Animais , Fármacos Anti-HIV/química , Antifúngicos/química , Antifúngicos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Proteínas Fúngicas/química , Proteínas Fúngicas/farmacologia , Humanos , Medicina Tradicional Chinesa , Proteínas de Plantas/química , Proteínas de Plantas/farmacologiaRESUMO
For centuries, mushrooms have been widely used as traditional Chinese medicine in Asia. Apart from polysaccharides and some small-molecule components, such as flavones, polyphenols and terpenes, mushrooms produce a large number of pharmaceutically active proteins, which have become popular sources of natural antitumor, antimicrobial, immunoenhancing agents. These bioactive proteins include lectins, laccases, Ribosome Inactivating Proteins (RIPs), nucleases, and Fungal Immunomodulatory Proteins (FIPs). The review is to summarize the characterstics of structure and bioactivities involved in antitumor, antiviral, antifungal, antibacterial and immunoenhancing activities of proteins from edible mushrooms, to better understand their mechanisms, and to direct research.
Assuntos
Agaricales , Proteínas Fúngicas , Agaricales/química , Animais , Anti-Infecciosos/química , Anti-Infecciosos/metabolismo , Anti-Infecciosos/farmacologia , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Proteínas Fúngicas/química , Proteínas Fúngicas/metabolismo , Proteínas Fúngicas/farmacologia , Humanos , FitoterapiaRESUMO
Bitter melon or bitter gourd (Momordica charantia) is a common vegetable in Asia and it is distinctive for its bitter taste. As an ingredient in folk medicine, research from different laboratories in recent years supports its potential medicinal applications with anti-tumor, anti-diabetic, anti-HIV activities in both in vitro and animal studies. In this short review, we summarize herein the recent progress in the antitumor aspect of bitter melon with a focus on the underlying molecular mechanisms. Further mechanistic studies as well as clinical trials are necessary to further verify its medicinal applications.
Assuntos
Antineoplásicos , Momordica charantia/química , Plantas Medicinais , Animais , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Humanos , Neoplasias/terapia , FitoterapiaRESUMO
Lectins are a group of proteins or glycoproteins with various potentially exploitable bioactivities and have been capturing more interest recently. They have been isolated and reported from various tissues of a diversity of plant species. Tubers are modified and enlarged plant structures derived from stems or roots that are used for nutrient storage and asexual reproduction. A number of plants such as yam, taro and potato are grown for their edible tubers, and lectins are found to be one of the major storage proteins. These lectins exhibit potent bioactivities encompassing mitogenic, antitumor, antimicrobial, immunomodulatory, antioxidative, hypoglycemic, insecticidal and nematicidal activities. They are potential resources for development into functional or healthy foods and targets for food protein researchers.
Assuntos
Lectinas/metabolismo , Arisaema/metabolismo , Dioscorea/metabolismo , Lectinas/química , Tubérculos/metabolismo , Solanum tuberosum/metabolismo , Trichosanthes/metabolismoRESUMO
The purpose of this account is to review the compounds capable of eliciting mitochondria-mediated apoptosis in cancer cells produced by medicinal fungi and plants. The medicinal fungi discussed encompass Cordyceps, Ganoderma species, Coriolus versicolor and Hypsizygus marmoreus. The medicinal plants discussed comprise Astragalus complanatus, Dendrobium spp, Dioscorea spp, Glycyrrhiza spp, Panax notoginseng, Panax ginseng, and Momordica charantia. These compounds have the potential of development into anticancer drugs.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Descoberta de Drogas , Fungos/química , Neoplasias/tratamento farmacológico , Plantas Medicinais/química , Antineoplásicos/síntese química , Antineoplásicos/isolamento & purificação , Proliferação de Células/efeitos dos fármacos , Fungos/metabolismo , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Neoplasias/metabolismo , Neoplasias/patologia , Plantas Medicinais/metabolismoRESUMO
The variety of proteins and peptides isolated from honey bee venom and wasp venom includes melittin, adiapin, apamine, bradykinin, cardiopep, mast cell degranulating peptide, mastoparan, phospholipase A2 and secapin. Some of the activities they demonstrate may find therapeutic applications.
Assuntos
Venenos de Abelha/farmacologia , Abelhas/metabolismo , Peptídeos/farmacologia , Venenos de Vespas/farmacologia , Vespas/metabolismo , Animais , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Venenos de Abelha/química , Humanos , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Venenos de Vespas/químicaRESUMO
A novel protein, designated as DOI, isolated from the Chinese yam (Dioscorea opposita Thunb.) could be the first protein drug for the treatment of menopausal syndrome and an alternative to hormone replacement therapy (HRT), which is known to have undesirable side effects. DOI is an acid- and thermo-stable protein with a distinctive N-terminal sequence Gly-Ile-Gly-Lys-Ile-Thr-Thr-Tyr-Trp-Gly-Gln-Tyr-Ser-Asp-Glu-Pro-Ser-Leu-Thr-Glu. DOI was found to stimulate estradiol biosynthesis in rat ovarian granulosa cells; induce estradiol and progesterone secretion in 16- to 18-month-old female Sprague Dawley rats by upregulating expressions of follicle-stimulating hormone receptor and ovarian aromatase; counteract the progression of osteoporosis and augment bone mineral density; and improve cognitive functioning by upregulating protein expressions of brain-derived neurotrophic factor and TrkB receptors in the prefrontal cortex. Furthermore, DOI did not stimulate the proliferation of breast cancer and ovarian cancer cells, which suggest it could be a more efficacious and safer alternative to HRT.
Assuntos
Dioscorea/metabolismo , Estradiol/biossíntese , Proteínas de Plantas/metabolismo , Sequência de Aminoácidos , Animais , Aromatase/genética , Aromatase/metabolismo , Densidade Óssea , Osso e Ossos/diagnóstico por imagem , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Feminino , Menopausa , Dados de Sequência Molecular , Osteoporose/prevenção & controle , Ovário/citologia , Peptídeos/química , Peptídeos/uso terapêutico , Proteínas de Plantas/química , Córtex Pré-Frontal/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor trkB/metabolismo , Receptores do FSH/genética , Receptores do FSH/metabolismo , Rizoma/metabolismo , Microtomografia por Raio-XRESUMO
Lectins (hemagglutinins) are defined as sugar-binding proteins or glycoproteins with various biological activities. A 60 kDa dimeric hemagglutinin with a blocked N-terminus was isolated in large yield (190 mg/60 g) from the common edible bean Phaseolus vulgaris cv. Hokkaido large pinto bean. Its hemagglutinating, antifungal, and antitumor activities as well as the effects of carbohydrate and metal ions on its hemagglutinating activity were examined. It inhibited the proliferation of nasopharyngeal carcinoma (CNE2), human breast cancer (MCF7), and hepatoma (HepG2) cells. The IC50 values toward HepG2, MCF7, and CNE2 cells after treatment for 48 h were 8.1, 6.07, and 7.49 µM, respectively, which were relatively low among lectins of different P. vulgaris cultivars. From the pinto beans, a 10888 Da antifungal peptide with similarity to plant defensins as revealed by mass spectroscopic analysis was also isolated with a yield of 3.2 mg of proteins from 60 g of beans. The large defensin was capable of inhibiting mycelial growth in Mycosphaerella arachidicola, Setosphaeria turcica, Bipolaris maydis, and Fusarium oxysporum but not in Valsa mali.
Assuntos
Antifúngicos/isolamento & purificação , Antifúngicos/farmacologia , Defensinas/farmacologia , Hemaglutininas/isolamento & purificação , Hemaglutininas/farmacologia , Phaseolus/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Antifúngicos/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Defensinas/química , Defensinas/isolamento & purificação , Fungos/efeitos dos fármacos , Fungos/crescimento & desenvolvimento , Hemaglutininas/química , Humanos , Micélio/efeitos dos fármacos , Micélio/crescimento & desenvolvimento , Extratos Vegetais/químicaRESUMO
In the present study, we isolated a novel hemagglutinin from an edible legume and explored its growth-inhibitory effect on osteocarcinoma and liver cancer cells. The protein was purified by liquid chromatography techniques which entailed affinity chromatography on Affi-gel blue gel, ion-exchange chromatography on Mono Q, and gel filtration on Superdex 75 with an FPLC system. The hemagglutinating activity of this hemagglutinin was demonstrated to be ion dependent and stable over a wide range of temperature and pH values. Antiproliferative activity was observed in the tumor cell lines MG-63 and HepG2 but not in the normal cell line WRL 68. Osteocarcinoma cells treated with the hemagglutinin underwent obvious cell shrinkage, chromatin condensation, mitochondrial membrane depolarization, and apoptosis. The mRNA expression level of interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-1 beta (IL-1ß), interferon-gamma (IFN-γ), and tumor necrosis factor alpha (TNF-α) were found to be up-regulated to different extents after treatment of this hemagglutinin.
Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Fabaceae/química , Hemaglutininas/isolamento & purificação , Hemaglutininas/farmacologia , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Antineoplásicos Fitogênicos/química , Apoptose/efeitos dos fármacos , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/fisiopatologia , Carcinoma/genética , Carcinoma/metabolismo , Carcinoma/fisiopatologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Hemaglutininas/química , Humanos , Interleucina-2/genética , Interleucina-2/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Extratos Vegetais/química , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Bakuchiol was an active antifungal compound isolated from Psoraleae Fructus by means of bioassay-guided fractionation in our previous study. The present work aimed to investigate the underlying mechanisms and the therapeutic effect of bakuchiol in Trichophyton mentagrophytes-induced tinea pedis. After exposure to bakuchiol at 0.25-fold, 0.5-fold and 1-fold of minimum inhibitory concentration (MIC) (3.91 µg/ml) for 24h, the fungal conidia of T. mentagrophytes demonstrated a significant dose-dependent increase in membrane permeability. Moreover, bakuchiol at 1-fold MIC elicited a 187% elevation in reactive oxygen species (ROS) level in fungal cells after a 3-h incubation. However, bakuchiol did not induce DNA fragmentation. In a guinea pig model of tinea pedis, bakuchiol at 1%, 5% or 10% (w/w) concentration in aqueous cream could significantly reduce the fungal burden of infected feet (p<0.01-0.05). In conclusion, this is the first report to demonstrate that bakuchiol is effective in relieving tinea pedis and in inhibiting the growth of the dermatophyte T. mentagrophytes by increasing fungal membrane permeability and ROS generation, but not via induction of DNA fragmentation.
Assuntos
Fenóis/farmacologia , Tinha dos Pés/tratamento farmacológico , Trichophyton/efeitos dos fármacos , Animais , Antifúngicos/farmacologia , Permeabilidade da Membrana Celular/efeitos dos fármacos , Fragmentação do DNA/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Cobaias , Testes de Sensibilidade Microbiana , Espécies Reativas de Oxigênio/metabolismo , Tinha dos Pés/microbiologia , Trichophyton/metabolismo , Trichophyton/patogenicidadeRESUMO
Breast cancer ranks as a common and severe neoplasia in women with increasing incidence as well as high risk of metastasis and relapse. Translational and laboratory-based clinical investigations of new/novel drugs are in progress. Medicinal plants are rich sources of biologically active natural products for drug development. The 27-kDa trichosanthin (TCS) is a ribosome inactivating protein purified from tubers of the Chinese herbal plant Trichosanthes kirilowii Maximowicz (common name Tian Hua Fen). In this study, we extended the potential medicinal applications of TCS from HIV, ferticide, hydatidiform moles, invasive moles, to breast cancer. We found that TCS manifested anti-proliferative and apoptosis-inducing activities in both estrogen-dependent human MCF-7 cells and estrogen-independent MDA-MB-231 cells. Flow cytometric analysis disclosed that TCS induced cell cycle arrest. Further studies revealed that TCS-induced tumor cell apoptosis was attributed to activation of both caspase-8 and caspase-9 regulated pathways. The subsequent events including caspase-3 activation, and increased PARP cleavage. With regard to cell morphology, stereotypical apoptotic features were observed. Moreover, in comparison with control, TCS- treated nude mice bearing MDA-MB-231 xenograft tumors exhibited significantly reduced tumor volume and tumor weight, due to the potent effect of TCS on tumor cell apoptosis as determined by the increase of caspase-3 activation, PARP cleavage, and DNA fragmentation using immunohistochemistry. Considering the clinical efficacy and relative safety of TCS on other human diseases, this work opens up new therapeutic avenues for patients with estrogen-dependent and/or estrogen-independent breast cancers.
Assuntos
Apoptose , Neoplasias da Mama/tratamento farmacológico , Tricosantina/farmacologia , Animais , Antineoplásicos/farmacologia , Caspase 3/metabolismo , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Proliferação de Células , Fragmentação do DNA , Ativação Enzimática , Feminino , Humanos , Concentração Inibidora 50 , Neoplasias Mamárias Animais/metabolismo , Medicina Tradicional Chinesa , Camundongos , Camundongos Nus , Transplante de Neoplasias , Extratos Vegetais/farmacologiaRESUMO
Medicinal plants of the Dendrobium genus are highly prized, and hence, methodologies have been developed to authenticate Dendrobium drugs from its adulterants. Many bioactive constituents of Dendrobium species have been identified. The macromolecules included lectins; the enzymes chalcone synthase, sucrose synthase, and cytokinin oxidase; and polysaccharides. The polysaccharides display immunomodulatory and hepatoprotective activities. Alkaloids exhibit antioxidant, anticancer, and neuroprotective activities. Other compounds manifest antioxidant, anticancer, and immunomodulatory.
Assuntos
Dendrobium/química , Medicina Tradicional/métodos , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Plantas Medicinais/química , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Produtos Biológicos/farmacologia , Humanos , Extratos Vegetais/químicaRESUMO
A 20-kDa Kunitz-type trypsin-chymotrypsin inhibitor, Bauhinia purpurea trypsin inhibitor (BPLTI), has been isolated from the seeds of B. purpurea L. by using liquid chromatography procedures that involved ion exchange chromatography on Sp-Sepharose and Mono S and gel filtration on Superdex 75. BPLTI demonstrated protease inhibitory activities of 7226 BAEE units/mg and 65 BTEE units/mg toward trypsin and α-chymotrypsin, respectively. BPLTI was relatively thermal (0-60°C) and pH (3-10) stable and its activity could be decreased by dithiothreitol treatment. BPLTI exhibited a wide spectrum of anti-proliferative and pro-apoptotic activities especially on human hepatocellular carcinoma Hep G2 cells. However, it was devoid of a significant antiproliferative effect on immortal human hepatic WRL 68 cells. We show here that BPLTI stimulates apoptosis in Hep G2 cells, including (1) evoking DNA damage including the production of chromatin condensation and apoptotic bodies; (2) induction of cell apoptosis/necrosis; (3) mitochondrial membrane depolarization; and (4) increasing the production of cytokines. Taken together, our findings show for the first time that purified protease inhibitor from B. purpurea L. seeds is a promising candidate for the treatment of human hepatocellular carcinoma.
Assuntos
Antineoplásicos/farmacologia , Bauhinia/química , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Extratos Vegetais/farmacologia , Antineoplásicos/isolamento & purificação , Apoptose/efeitos dos fármacos , Células Hep G2 , Humanos , Extratos Vegetais/isolamento & purificação , Sementes/química , Inibidores da Tripsina/isolamento & purificação , Inibidores da Tripsina/farmacologia , Células Tumorais CultivadasRESUMO
The incidence of nasopharyngeal carcinoma (NPC) remains high in endemic regions, including southern China, northern Africa, and North America. One of the promising therapeutic approaches on NPC is drug screening from natural products, such as components from traditional Chinese medicine. In this study, the antitumor activity of Momordica charantia lectin (MCL), a type II ribosome inactivating protein from bitter gourd, on NPC was investigated. MCL evinced potent cytotoxicity toward NPC CNE-1 (IC(50) = 6.9) and CNE-2 (IC(50) = 7.4) cells but minimally affected normal NP 69 cells. Further investigation disclosed that MCL induced apoptosis, DNA fragmentation, G(1)-phase arrest, and mitochondrial injury in both types of NPC cells. The reduction of cyclin D1 and phosphoretinoblastoma (Rb) protein expression contributed to arrest at G(1)-phase of the cell cycle. These events were associated with regulation of mitogen-activated protein kinases (MAPK; including p38 MAPK, JNK, and ERK) phosphorylation and promoted downstream nitric oxide (NO) production. Concurrent administration of the p38 MAPK inhibitor SB-203580 significantly diminished NO production and lethality of MCL toward NPC cells. Further studies revealed that MCL increased cytochrome c release into the cytosol, activated caspases-8, -9, and -3, and enhanced production of cleaved PARP, subsequently leading to DNA fragmentation and apoptosis. Finally, an intraperitoneal injection of MCL (1.0 mg/kg/d) led to an average of 45% remission of NPC xenograft tumors subcutaneously inoculated in nude mice. This is the first article that unveils the potential of a type II RIP, MCL, for prevention and therapy of NPC.
Assuntos
Antineoplásicos/farmacologia , Carcinoma/tratamento farmacológico , Lectinas/química , Momordica charantia/metabolismo , Neoplasias Nasofaríngeas/tratamento farmacológico , Extratos Vegetais/metabolismo , Extratos Vegetais/farmacologia , Proteínas Inativadoras de Ribossomos/química , Animais , Linhagem Celular Tumoral , Fragmentação do DNA , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Humanos , Técnicas In Vitro , Concentração Inibidora 50 , Sistema de Sinalização das MAP Quinases , Potenciais da Membrana , Camundongos , Camundongos Nus , Transplante de Neoplasias , Fosforilação , Indução de RemissãoRESUMO
This study aimed to investigate the mechanism of Dendrobium candidum extract in promoting expression of aquaporin-5 for treatment of Sjögren's syndrome (SS). Sixteen patients with SS suffered from deficient secretion of saliva due to an autoimmune destruction of salivary glands leading to dry mouth symptoms (xerostomia). However, glandular dysfunction also occurred without destruction. Based upon its abnormal distribution in SS salivary glands, a potential role of the water channel protein aquaporin-5 (AQP-5) in the pathogenesis of SS was proposed. After oral administration of D. candidum extracted liquid (DCEL) for 1 week, saliva and salivary gland biopsies from labial glands of patients were collected and examined by employing immunoreactivity and immunohistochemistry techniques. Results showed that salivary secretion increased by about 65% in patients treated with DCEL as compared with the control group. Higher labeling indices (percentage of acinus area immunoreactive for AQP-5) in the biopsies were found in SS patients who had taken DCEL. This study demonstrated that D. candidum would regulate the expression of AQP-5 in labial glands of SS patients and thereby promoted secretion of saliva to improve dry mouth symptoms.