RESUMO
Gastric cancer (GC) has high incidence rates and constitutes a common cause of cancer mortality. Despite advances in treatment, GC remains a challenge in cancer therapy which is why novel treatment strategies are needed. The interest in natural compounds has increased significantly in recent years because of their numerous biological activities, including anti-cancer action. The isolation of the bioactive compounds from Coptis chinensis Franch was carried out with the Centrifugal Partition Chromatography (CPC) technique, using a biphasic solvent system composed of chloroform (CHCl3)-methanol (MeOH)-water (H2O) (4:3:3, v/v) with an addition of hydrochloric acid and trietylamine. The identity of the isolated alkaloids was confirmed using a high resolution HPLC-MS chromatograph. The phytochemical constituents of Coptis chinensis such as berberine, jatrorrhizine, palmatine and coptisine significantly inhibited the viability and growth of gastric cancer cell lines ACC-201 and NCI-N87 in a dose-dependent manner, with coptisine showing the highest efficacy as revealed using MTT and BrdU assays, respectively. Flow cytometry analysis confirmed the coptisine-induced population of gastric cancer cells in sub-G1 phase and apoptosis. The combination of coptisine with cisplatin at the fixed-ratio of 1:1 exerted synergistic and additive interactions in ACC-201 and NCI-N87, respectively, as determined by means of isobolographic analysis. In in vivo assay, coptisine was safe for developing zebrafish at the dose equivalent to the highest dose active in vitro, but higher doses (greater than 10 times) caused morphological abnormalities in larvae. Our findings provide a theoretical foundation to further studies on more detailed mechanisms of the bioactive compounds from Coptis chinensis Franch anti-cancer action that inhibit GC cell survival in in vitro settings.
Assuntos
Alcaloides , Alcaloides de Berberina , Berberina , Coptis , Medicamentos de Ervas Chinesas , Neoplasias Gástricas , Alcaloides/análise , Alcaloides/farmacologia , Animais , Berberina/análogos & derivados , Berberina/farmacologia , Alcaloides de Berberina/farmacologia , Bromodesoxiuridina , Clorofórmio , Cisplatino , Coptis/química , Coptis chinensis , Medicamentos de Ervas Chinesas/química , Ácido Clorídrico , Isoquinolinas , Metanol , Solventes , Neoplasias Gástricas/tratamento farmacológico , Água , Peixe-ZebraRESUMO
Palmatine (PLT) is a natural isoquinoline alkaloid that belongs to the class of protoberberines and exhibits a wide spectrum of pharmacological and biological properties, including anti-cancer activity. The aim of our study was to isolate PLT from the roots of Berberis cretica and investigate its cytotoxic and anti-proliferative effects in vitro alone and in combination with doxorubicine (DOX) using human ER+/HER2- breast cancer cell lines. The alkaloid was purified by column chromatography filled with silica gel NP and Sephadex LH-20 resin developed in the mixture of methanol: water (50:50 v/v) that provided high-purity alkaloid for bioactivity studies. The purity of the alkaloid was confirmed by high resolution mass measurement and MS/MS fragmentation analysis in the HPLC-ESI-QTOF-MS/MS-based analysis. It was found that PLT treatment inhibited the viability and proliferation of breast cancer cells in a dose-dependent manner as demonstrated by MTT and BrdU assays. PLT showed a quite similar growth inhibition on breast cancer cells with IC50 values ranging from 5.126 to 5.805 µg/mL. In contrast, growth of normal human breast epithelial cells was not affected by PLT. The growth inhibitory activity of PLT was related to the induction of apoptosis, as determined by Annexin V/PI staining. Moreover, PLT sensitized breast cancer cells to DOX. Isobolographic analysis revealed synergistic and additive interactions between studied agents. Our studies suggest that PLT can be a potential candidate agent for preventing and treating breast cancer.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Alcaloides de Berberina/farmacologia , Neoplasias da Mama/tratamento farmacológico , Antineoplásicos Fitogênicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Apoptose/efeitos dos fármacos , Alcaloides de Berberina/administração & dosagem , Berberis/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/administração & dosagem , Sinergismo Farmacológico , Feminino , Humanos , Células MCF-7 , Fitoterapia , Raízes de Plantas/química , Plantas Medicinais/química , Receptores de Estrogênio/metabolismoRESUMO
Gastric cancer belongs to the heterogeneous malignancies and, according to the World Health Organization, it is the fifth most commonly diagnosed cancer in men. The aim of this review is to provide an overview on the role of natural products of plant origin in the therapy of gastric cancer and to present the potentially active metabolites which can be used in the natural therapeutical strategies as the support to the conventional treatment. Many of the naturally spread secondary metabolites have been proved to exhibit chemopreventive properties when tested on the cell lines or in vivo. This manuscript aims to discuss the pharmacological significance of both the total extracts and the single isolated metabolites in the stomach cancer prevention and to focus on their mechanisms of action. A wide variety of plant-derived anticancer metabolites from different groups presented in the manuscript that include polyphenols, terpenes, alkaloids, or sulphur-containing compounds, underlines the multidirectional nature of natural products.
Assuntos
Fitoterapia/métodos , Extratos Vegetais/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Alcaloides/farmacologia , Animais , Produtos Biológicos/farmacologia , Humanos , Fitoterapia/tendências , Extratos Vegetais/metabolismo , Polifenóis/farmacologia , Neoplasias Gástricas/terapia , Terpenos/farmacologiaRESUMO
Naturally occurring coumarins are bioactive compounds widely used in Asian traditional medicine. They have been shown to inhibit proliferation, induce apoptosis, and/or enhance the cytotoxicity of currently used drugs against a variety of cancer cell types. The aim of our study was to examine the antiproliferative activity of different linear furanocoumarins on human rhabdomyosarcoma, lung, and larynx cancer cell lines, and dissolve their cellular mechanism of action. The coumarins were isolated from fruits of Angelica archangelica L. or Pastinaca sativa L., and separated using high-performance counter-current chromatography (HPCCC). The identity and purity of isolated compounds were confirmed by HPLC-DAD and NMR analyses. Cell viability and toxicity assessments were performed by means of methylthiazolyldiphenyl-tetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays, respectively. Induction of apoptosis and cell cycle progression were measured using flow cytometry analysis. qPCR method was applied to detect changes in gene expression. Linear furanocoumarins in a dose-dependent manner inhibited proliferation of cancer cells with diverse activity regarding compounds and cancer cell type specificity. Imperatorin (IMP) exhibited the most potent growth inhibitory effects against human rhabdomyosarcoma and larynx cancer cell lines owing to inhibition of the cell cycle progression connected with specific changes in gene expression, including CDKN1A. As there are no specific chemotherapy treatments dedicated to laryngeal squamous cell carcinoma and rhabdomyosarcoma, and IMP seems to be non-toxic for normal cells, our results could open a new direction in the search for effective anti-cancer agents.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Furocumarinas/farmacologia , Neoplasias Laríngeas/patologia , Rabdomiossarcoma/patologia , Angelica archangelica/química , Apoptose , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Cromatografia , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Fibroblastos/efeitos dos fármacos , Citometria de Fluxo , Frutas/química , Humanos , L-Lactato Desidrogenase/metabolismo , Neoplasias Laríngeas/tratamento farmacológico , Pastinaca/química , Rabdomiossarcoma/tratamento farmacológicoRESUMO
Three curcuminoids: bisdemethoxycurcumin, demethoxycurcumin, and curcumin from turmeric were successfully separated by a high capacity solvent system composed of heptane: chloroform: methanol: water mixture (5: 6: 3: 2 v/v/v/v) tailored for centrifugal partition chromatographs at K-values of 0.504, 1.057, 1.644, respectively. These three ferulic acid derivatives obtained at a purity rate exceeding 95% were analysed by an HPLC-MS spectrometer. Turmeric extract inhibited the proliferation/viability of A549 human lung cancer, HT29 colon cancer, and T98G glioblastoma cell lines in (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) tetrazolium reduction assay (MTT). Single curcuminoids significantly decreased the viability/proliferation of lung cancer cells in a dose-dependent manner. However, total extract displayed the superior anticancer activity in the investigated cell lines. Crude extract in combination with cisplatin augmented the decrease in the viability of cancer cells compared with single compound treatment in A549 lung cancer cells. Total extract of Curcuma longa could be regarded as being more effective against lung cancer cells in vitro than its separated compounds.
Assuntos
Antineoplásicos Fitogênicos , Curcuma/química , Curcumina/análogos & derivados , Neoplasias/tratamento farmacológico , Extratos Vegetais/farmacologia , Células A549 , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Linhagem Celular Tumoral , Fracionamento Químico/métodos , Cromatografia Líquida de Alta Pressão/métodos , Ácidos Cumáricos/química , Curcumina/química , Curcumina/farmacologia , Curcumina/uso terapêutico , Diarileptanoides , Células HT29 , Humanos , Espectrometria de Massas/métodos , Neoplasias/patologia , Fitoterapia/métodos , Extratos Vegetais/uso terapêutico , SolventesRESUMO
Coumarins are a group of naturally occurring compounds common in the plant world. These substances and their derivatives exhibit a broad range of biological activities. One of the naturally occurring coumarins is osthole, which can most frequently be found in plants of the Apiaceae family. Cnidium monnieri (L.) Cusson ex Juss. Angelica pubescens Maxim. and Peucedanum ostruthium (L.). It has anti-proliferative, anti-inflammatory, anti-convulsant, and antiallergic properties; apart from that, inhibition of platelet aggregation has also been proved. The impact of osthole on bone metabolism has been demonstrated; also its hepatoprotective and neuroprotective properties have been confirmed. The inhibitory effect of this metokcompound on the development of neurodegenerative diseases has been proved in experimental models. Anticancer features of osthole have been also demonstrated both in vitro on different cell lines, and in vivo using animals xenografts. Osthole inhibited proliferation, motility and invasiveness of tumor cells, which may be associated with the induction of apoptosis and cell cycle slowdown. The exact molecular mechanism of osthole anti-cancer mode of action has not been fully elucidated. A synergistic effect of osthole with other anti-tumor substances has been also reported. Modification of its chemical structure led to the synthesis of many derivatives with significant anticancer effects. To sum up, osthole is an interesting therapeutic option, due to both its direct effect on tumor cells, as well as its neuroprotective or anti-inflammatory properties. Thus, there is a chance to use osthole or its synthetic derivatives in the treatment of cancer.
Assuntos
Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Cumarínicos/farmacologia , Fármacos Neuroprotetores/farmacologia , Animais , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cnidium/química , Cumarínicos/uso terapêutico , Humanos , Extratos Vegetais/químicaRESUMO
BACKGROUND: Coumarins are a large group of naturally-occurring compounds with a wide range of biological properties, including anticancer activity. 7-Substituted coumarins (umbelliferone, scoparone, and herniarin) were analyzed for their potential anticancer activity against laryngeal cancer cells (LCC). MATERIALS AND METHODS: High-performance counter-current chromatography was applied for successful separation of umbelliferone from fruits of Heracleum leskowii. A two-phase solvent system composed of n-heptane-methanol-ethyl acetate-water (1:2:1:2, v/v/v) was successfully used. Cell proliferation was assessed after 48-72 h by means of MTT test, and tumor cell motility by a wound assay model. Measurement of cell death was estimated using enzyme-linked immunosorbent assay (ELISA), and cell-cycle analysis was performed by flow cytometry. Extracellular signal-regulated kinases-1/2 (ERK1/2) and AKT kinase activation status were analyzed by western blotting. RESULTS: Umbelliferone, scoparone, and, to a lesser extent, herniarin reduced viability and migration of RK33 LCC in a dose-dependent manner. Scoparone and herniarin were found to induce apoptosis of LCC. None of the tested compounds influenced the ERK1/2 and AKT kinase activity, nor significantly affected cell-cycle progression in the LCC line studied. CONCLUSION: Our findings suggest the therapeutic potential of 7-substituted coumarins in the treatment of laryngeal cancer.