RESUMEN
Tauroursodeoxycholic acid (TUDCA) is approved for the treatment of liver diseases. However, the antihyperglycemic effects/mechanisms of TUDCA are still less clear. The present study aimed to evaluate the antidiabetic action of TUDCA in streptozotocin (STZ)-induced type 2 diabetes mellitus (T2DM) in rats. Fifteen adult Wistar albino male rats were randomly divided into three groups (n = five in each): control, diabetic (STZ), and STZ+TUDCA. The results showed that TUDCA treatment significantly reduced blood glucose, HbA1c%, and HOMA-IR as well as elevated the insulin levels in diabetic rats. TUDCA therapy increased the incretin GLP-1 concentrations, decreased serum ceramide synthase (CS), improved the serum lipid profile, and restored the glycogen content in the liver and skeletal muscles. Furthermore, serum inflammatory parameters (such as TNF-α, IL-6, IL-1ß, and PGE-2) were substantially reduced with TUDCA treatment. In the pancreas, STZ+TUDCA-treated rats underwent an obvious enhancement of enzymatic (CAT and SOD) and non-enzymatic (GSH) antioxidant defense systems and a marked decrease in markers of the lipid peroxidation rate (MDA) and nitrosative stress (NO) compared to STZ-alone. At the molecular level, TUDCA decreased the pancreatic mRNA levels of iNOS and apoptotic-related factors (p53 and caspase-3). In conclusion, TUDCA may be useful for diabetes management and could be able to counteract diabetic disorders via anti-hyperlipidemic, antioxidant, anti-inflammatory, and anti-apoptotic actions.
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Apoptosis , Diabetes Mellitus Experimental , Inflamación , Estrés Oxidativo , Ratas Wistar , Ácido Tauroquenodesoxicólico , Animales , Ácido Tauroquenodesoxicólico/farmacología , Estrés Oxidativo/efectos de los fármacos , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Apoptosis/efectos de los fármacos , Ratas , Masculino , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Estreptozocina , Glucemia/metabolismo , Glucemia/efectos de los fármacos , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Hígado/metabolismo , Hígado/efectos de los fármacos , Hígado/patologíaRESUMEN
Hepatocellular carcinoma (HCC) is one of the world's most risky diseases due to the lack of clear and cost-effective therapeutic targets. Currently, the toxicity of conventional chemotherapeutic medications and the development of multidrug resistance is driving research into targeted therapies. The nano-biomedical field's potential for developing an effective therapeutic nano-sized drug delivery system is viewed as a significant pharmaceutical trend for the encapsulation and release of numerous anticancer therapies. In this regard, current research is centered on the creation of biodegradable chitosan nanoparticles (CSNPs) for the selective and sustained release of bee venom into liver cancer cells. Furthermore, surface modification with polyethylene glycol (PEG) and GE11 peptide-conjugated bee venom-CSNPs allows for the targeting of EGFR-overexpressed liver cancer cells. A series of in vitro and in vivo cellular analyses were used to investigate the antitumor effects and mechanisms of targeted bee venom-CSNPs. Targeted bee venom-CSNPs, in particular, were found to have higher cytotoxicity against HepG2 cells than SMMC-7721 cells, as well as stronger cellular uptake and a substantial reduction in cell migration, leading to improved cancer suppression. It also promotes cancer cell death in EGFR overexpressed HepG2 cells by boosting reactive oxygen species, activating mitochondria-dependent pathways, inhibiting EGFR-stimulated MEK/ERK pathway, and elevating p38-MAPK in comparison to native bee venom. In hepatocellular carcinoma (HCC)-induced mice, it has anti-cancer properties against tumor tissue. It also improved liver function and architecture without causing any noticeable toxic side effects, as well as inhibiting tumor growth by activating the apoptotic pathway. The design of this cancer-targeted nanoparticle establishes GE11-bee venom-CSNPs as a potential chemotherapeutic treatment for EGFR over-expressed malignancies. Finally, our work elucidates the molecular mechanism underlying the anticancer selectivity of targeted bee venom-CSNPs and outlines therapeutic strategies to target liver cancer.
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Venenos de Abeja , Carcinoma Hepatocelular , Quitosano , Neoplasias Hepáticas , Nanopartículas , Animales , Venenos de Abeja/farmacología , Venenos de Abeja/uso terapéutico , Carcinoma Hepatocelular/patología , Quitosano/uso terapéutico , Receptores ErbB/metabolismo , Neoplasias Hepáticas/patología , Sistema de Señalización de MAP Quinasas , Ratones , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Péptidos/metabolismoRESUMEN
Prostate cancer is still at the forefront causes of cancer-related morbidity and mortality in men throughout the globe. The disease is initiated and fostered by a subset of cancer stem cells (CSCs). Costus speciosus is an oriental herb used in traditional medicine and is a source of bioactive compounds with known pharmacological activities. The present study aims to evaluate the anticancer property of varied extracts isolated from C. speciosus against the human prostate cancer PC-3 cells. Extracts derived from C. speciosus were analyzed by chromatography-mass spectrometry and their effects on the proliferation, migration, invasion, apoptosis and cell cycle distribution of PC-3 cells were investigated. Results showed that crude hexane extract of C. speciosus (CHECS) inhibited proliferation, clonogenic and metastatic potential of PC-3 cells. It induced apoptosis in PC-3 cells associated with generation of reactive oxygen species (ROS), reduction of GSH and permeabilization of mitochondrial and lysosomal membranes, induction of caspase-9/-3 activity and PARP-1 cleavage, DNA damage and an increase in ratio of Bax/Bcl-2 proteins. CHECS induced G0/G1 and G2/M arrest in PC-3 cells and targeted PC-3 prostaspheres. These findings indicate that phytochemicals of CHECS exhibit potential for natural therapeutic product development for prostate cancer.
RESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: The medicinal herb, Anethum graveolens L. (dill) is one of the potent culinary herbs used as an alternative form of medicine worldwide. The unguent topical Oil from the aerial parts of A. graveolens was found to be effective in the management of uterus cancer in ethnomedicine has been reported. BACKGROUND: The incidence and mortality rates of Hepatocellular carcinoma (HCC) are steadily rising worldwide, especially, in underdeveloped and developing countries. Moreover, HCC develops rapidly in patients with chronic cirrhosis or hepatitis, where the solid tumours/malignancies coexist with the inflammation. Recent studies have shown that the medicinal herb, Anethum graveolens, holds anticancer potential, which could be a promising approach for the treatment of various tumours. AIM: In the current study, we have analysed the antiproliferative effect of ethyl acetate fraction of Dill Seeds (EAFD) on HepG2 cell line. METHODS: Cell viability and proliferation were observed by MTT assay; Morphological changes were studied using fluorescent stains like Hoechst 33342, acridine orange/ethidium bromide and JC-1 dye. Further, the pro-apoptotic activity was demonstrated through Annexin-V-FITC/ PI assay and cell cycle analysis. Different concentrations (0.1, 0.2, 0.4, 0.6, 0.8â¯mg/ml) of EAFD were studied. RESULTS: EAFD markedly suppressed the proliferation of HepG2 cells in a dose and time-dependent manner. The phase contrast and fluorescence microscopy revealed the morphological alterations like disruption, shrinkage, detachment and blebbing of cell membrane accompanied by nuclear condensation after exposure to EAFD. Radical scavenging activity was evidenced by measurement of ROS levels post-treatment. Modulation of mitochondrial membrane potential was exhibited leading to the activation of caspases 3/7 and 9 which is a committed step towards apoptosis. Annexin V-FITC/ PI assay and cell cycle, later confirmed the apoptosis and cell cycle arrest in 'G2/M' phase through flow cytometric analysis. CONCLUSION: In conclusion, a significant apoptogenic effect was exhibited by EAFD against HepG2 cells in inducing apoptosis and cell cycle arrest. Our findings indicate that the medicinal herb- Anethum graveolens, holds potential in treating hepatocellular carcinoma effectively.
Asunto(s)
Anethum graveolens , Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Aceites de Plantas/farmacología , Plantas Medicinales , Antineoplásicos Fitogénicos/aislamiento & purificación , Apoptosis/fisiología , Puntos de Control del Ciclo Celular/fisiología , Proliferación Celular/efectos de los fármacos , Proliferación Celular/fisiología , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Relación Dosis-Respuesta a Droga , Células Hep G2 , Humanos , Aceites de Plantas/aislamiento & purificación , SemillasRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Phoenix dactylifera L. (Ajwa date) has high nutritive value and are consumed in Arabian Peninsula as an essential diet. Phoenix dactylifera L. have been mentioned in folk remedies of traditional Egyptian medicine and alternative medicine, for numerous health benefits including cancer treatment. The aim of the study is to evaluate the anticancer effects of the extract of Ajwa Date on human Prostate cancer cell line (PC3). MATERIALS AND METHODS: Antiproliferative effect was measured using MTT assay. The long-term effect of EAFAD was determined using colony assay. Different stains like Giemsa and fluorescent stains (DAPI and acridine orange / Ethidium bromide) measured morphological changes. Loss of mitochondrial membrane potential and increased oxidative stress were measured using JC-1 and DCFH-DA dyes. DNA degradation was analyzed by comet assay. Cell cycle distribution was measured by flow cytometer. The apoptotic cell was quantified by annexin V-FITC and Propidium iodide dual staining using flow cytometer. RESULTS: PC3 cell line was treated with ethyl acetate fractions of Ajwa dates (EAFAD) to study their morphological and cellular changes and induction of apoptosis. MTT assay showed the strong inhibitory effect of EAFAD on PC3 cells. Loss of mitochondrial membrane potential and increased oxidative stress were observed in EAFAD treated cells, which suggested mitochondrial involvement in apoptosis. Comet assay proved DNA fragmentation induced by EAFAD. Flow Cytometer results demonstrated that Annexin V-FITC and propidium iodide staining showed that EAFAD induced apoptosis and arrest the cell cycle in S phase. CONCLUSION: Our results suggested EAFAD has potential therapeutics properties for prostate cancer.
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Antineoplásicos Fitogénicos/farmacología , Phoeniceae , Extractos Vegetales/farmacología , Acetatos/química , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular , Línea Celular Tumoral , Fragmentación del ADN , Humanos , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Solventes/químicaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Foeniculum vulgare Mill. (Fennel) is one of the most common herbs used in alternative medicines for its varied range of bioactivity. In Ecuador (South America), use of fennel in traditional cancer treatment is on record. AIM OF THE STUDY: The objective of the present study was to demonstrate the anti-proliferative and apoptotic effect of chloroform fraction of fennel (CFF) in MCF-7 cells. MATERIALS AND METHODS: Anti-proliferative assay (MTT assay) and colony formation assay were performed to study the growth inhibitory effect of CFF. Various morphological changes of apoptosis were observed using Giemsa, Hoechst and Acridine orange/ ethidium bromide stains in MCF-7 cells. The extent of apoptosis and cell cycle arrest was measured by flow cytometer. Levels of ROS and mitochondrial membrane potential was measured by DCFH-DA and JC-1 respectively. Caspases activity was measured by luminescence and DNA fragmentation by comet assay. RESULTS: CFF appeared as a good inhibitor of growth against MCF-7 and MDA-MB-237 in time- and concentration-dependent manners. All the morphological changes of apoptosis were evident in treatment groups. Annexin V/PI-assay of apoptosis gave around 49% of apoptotic cells upon treatment of 0.5â¯mg/ml of CFF and PI-stained cells showed the G1 phase cell cycle arrest. Elevated levels of ROS, disrupted mitochondrial membrane, increased levels of caspase-9 & caspase-3 and DNA fragmentation were noted in treated MCF-7 cells. CONCLUSION: Our findings revealed the proliferation inhibition, cell cycle arrest and apoptosis induction effect of CFF, which may help in exploring the novel anti-cancer drug for therapeutic implications.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Foeniculum , Extractos Vegetales/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Caspasa 3/metabolismo , Caspasa 9/metabolismo , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Cloroformo/química , Ensayo Cometa , Humanos , Células MCF-7 , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/fisiología , Especies Reactivas de Oxígeno/metabolismo , Semillas , Solventes/químicaRESUMEN
BACKGROUND: Prostate cancer-associated mortality is increasing at an alarming rate, which highlights the inevitability for unearthing novel agent for the management of this disease. Anethole, a major constituent of Foeniculum vulgare (fennel) essential oil, is widely used in folk medicine; it possesses anti-oxidant, antiinflammatory, anti-proliferative and tumoricidal potentialities. OBJECTIVE: The current research was conducted to assess the impact of anethole on prostate cancer cell line, PC- 3, and to delineate the molecular mechanism of action. METHODS: To achieve this aim, the growth-inhibitory effect of anethole was evaluated by MTT assay. Apoptotic death and cell cycle analyses were assessed by flow cytometry and alterations in gene expression were investigated by qPCR and Western blot analyses. RESULTS: The observations indicated that anethole inhibited proliferation, clonal growth and migration of PC-3 cells. It also suppressed growth of PC-3 derived cancer stem cells (tumorspheres). Pro-apoptotic potential of anethole was accompanied by generation of ROS, permeabilization of the mitochondrial and lysosomal membranes, activation of caspase-3 and -9, DNA damage, PARP cleavage and induction of Bax/Bcl-2 protein ratio. Further, anethole induced G2/M phase arrest, downregulation of cyclins D1, CDK-4 and c-Myc proteins and upregulation of p21 and p27. Anethole suppressed nuclear localization of NF-κB protein and downregulated transcription of NF-κB-dependent genes. CONCLUSION: Overall, the above findings highlight the effectiveness of anethole as a potential candidate for prostate cancer therapy.
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Anisoles/farmacología , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Neoplasias de la Próstata/tratamiento farmacológico , Derivados de Alilbenceno , Anisoles/química , Antineoplásicos/química , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Daño del ADN , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Masculino , Estructura Molecular , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Relación Estructura-ActividadRESUMEN
There is an urgent need to improve the clinical management of hepatocellular carcinoma (HCC), one of the most common causes of global cancer-related deaths. Zingibar officinale is a medicinal herb used throughout history for both culinary and medicinal purposes. It has antioxidant, anticarcinogenic, and free radical scavenging properties. Previously, we proved that the crude flavonoid extract of Z. officinale (CFEZO) inhibited growth and induced apoptosis in several cancer cell lines. However, the effect of the CFEZO on an HCC cell line has not yet been evaluated. In this study, we explored the anticancer activity of CFEZO against an HCC cell line, HepG2. CFEZO significantly inhibited proliferation and induced apoptosis in HepG2 cells. Typical apoptotic morphological and biochemical changes, including cell shrinkage and detachment, nuclear condensation and fragmentation, DNA degradation, and comet tail formation, were observed after treatments with CFEZO. The apoptogenic activity of CFEZO involved induction of ROS, depletion of GSH, disruption of the mitochondrial membrane potential, activation of caspase 3/9, and an increase in the Bax/Bcl-2 ratio. CFEZO treatments induced upregulation of p53 and p21 expression and downregulation of cyclin D1 and cyclin-dependent kinase-4 expression, which were accompanied by G2/M phase arrest. These findings suggest that CFEZO provides a useful foundation for studying and developing novel chemotherapeutic agents for the treatment of HCC.
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Antineoplásicos Fitogénicos/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Flavonoides/farmacología , Neoplasias Hepáticas/tratamiento farmacológico , Zingiber officinale/química , Apoptosis/efectos de los fármacos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Caspasa 3/metabolismo , Caspasa 9/metabolismo , Proliferación Celular/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Glutatión/metabolismo , Células HeLa , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Células MCF-7 , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Plantas Medicinales/química , Especies Reactivas de Oxígeno/metabolismoRESUMEN
AIM: Cis-diammine dichloroplatinum (CDDP) is one of the most important chemotherapeutic agents for cancer treatment. Nonetheless, its notable side effect, nephrotoxicity, undermines its clinical use. The current study was undertaken to evaluate the protective potential of the aqueous extract (AEC) of Cinnamomum cassia (cinnamon) against the cytotoxic effect of CDDP in vitro and to elaborate the molecular mechanism underlying protection. METHODS: MTT assay was performed to assess viability of the normal kidney Vero cells treated with CDDP and/or AEC. Cells were stained with Coomassie blue, acridine orange and ethidium bromide to highlight morphological features of apoptosis. Caspase-3 activity, DNA fragmentation and reactive oxygen species (ROS) level were monitored to assess biochemical hallmarks of apoptosis. Quantitative RT-PCR and Western blot analyses were performed to elucidate expression of cellular molecules underlying the protective potential of AEC. RESULTS: CDDP-treated Vero cells exhibited hallmarks of apoptosis; these hallmarks were significantly suppressed in the presence of AEC. AEC did not alter activity of CDDP-induced cytotoxicity of breast and liver cancer cells. AEC treatment of Vero cells prevented CDDP-induced increased expression of mitochondrial Bax protein, release of mitochondrial cytochrome c, caspase-3 activation, DNA fragmentation and generation of ROS. AEC up-regulated expression of the cytoprotective gene (heme oxygenase (HO)-1). CONCLUSION: These findings suggest AEC has protective effects against CDDP-induced toxicity via preventing the activation of various cellular mechanisms mediating apoptotic cell death, without compromising the anticancer efficiency of CDDP. Thus, cinnamon may represent one of the most feasible ways to reduce the risk of CDDP-induced toxicity.
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Antineoplásicos/toxicidad , Cinnamomum zeylanicum , Cisplatino/toxicidad , Enfermedades Renales/prevención & control , Corteza de la Planta , Extractos Vegetales/farmacología , Animales , Apoptosis/efectos de los fármacos , Caspasa 3/metabolismo , Chlorocebus aethiops , Citocromos c/metabolismo , Fragmentación del ADN/efectos de los fármacos , Enfermedades Renales/inducido químicamente , Fitoterapia/métodos , Especies Reactivas de Oxígeno/metabolismo , Regulación hacia Arriba , Células Vero , Proteína X Asociada a bcl-2/metabolismoRESUMEN
BACKGROUND: Colorectal cancer (CRC) is a major cause of morbidity and mortality, being the second most common type of cancer worldwide in both men and women. It accounts yearly for approximately 9% of all new cases of cancers. Furthermore, the current chemotherapeutic regimens seem unsatisfactory, so that exploration of novel therapeutic modalities is needed. The present study was undertaken to investigate the inhibitory effects of a crude alkaloid extract (CAERS) of a medicinal herb, Rhazya stricta, on proliferation of CRC HCT116 cells and to elucidate mechanisms of action. To achieve these aims, we utilized MTT, comet, DNA laddering and gene reporter assays, along with Western blot and RT-PCR analyses. RESULTS: We found that CAERS inhibited cell proliferation and induced apoptotic cell death in HCT116 cells. Hallmarks of morphological and biochemical signs of apoptosis were clearly evident. CAERS down-regulated DNA-binding and transcriptional activities of NF-κB and AP-1 proteins, while up-regulating expression of the Nrf-2 protein. It also down-regulated expression levels of the ERK MAPK, Bcl-2, cyclin D1, CDK-4, survivin and VEGF and up-regulated levels of Bax, caspase-3/7 and -9, p53, p21, Nrf-2. Markedly, it promoted mRNA expression levels of cytoprotective genes including the hemeoxygenase-1, NAD(P)H quinine oxidoreductase 1 and UDP-glucuronyltransferase. CONCLUSIONS: These findings indicate that CAERS exerts antiproliferative action on CRC cells through induction of apoptotic mechanisms, and suggest CAERS could be a promising agent for studying and developing novel chemotherapeutic agents aimed at novel molecular targets for the treatment of CRC.
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Apocynaceae/química , Apoptosis/efectos de los fármacos , Neoplasias del Colon/patología , Citoprotección/genética , FN-kappa B/metabolismo , Extractos Vegetales/farmacología , Factor de Transcripción AP-1/metabolismo , Western Blotting , Proliferación Celular/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/metabolismo , Femenino , Humanos , Masculino , FN-kappa B/genética , Plantas Medicinales/química , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Transcripción AP-1/genética , Células Tumorales CultivadasRESUMEN
BACKGROUND AND AIMS: Colorectal cancer is one of the leading causes of death in the world. The aim of this study was to investigate the growth-suppression potentiality of a crude saponin extract (CSENS) prepared from medicinal herb, Nigella sativa, on human colon cancer cells, HCT116. MATERIALS AND METHODS: HCT116 cells were subjected to increasing doses of CSENS for 24, 48 and 72 h, and then harvested and assayed for cell viability by WST-1. Flow cytometry analyses, cell death detection ELISA, fluorescent stains (Hoechst 33342 and acridine orange/ethidium bromide), DNA laddering and comet assays were carried out to confirm the apoptogenic effects of CSENS. Luciferase reporter gene assays, quantitative reverse transcription-polymerase chain reaction and Western blot analyses were performed to assess the impact of CAERS and CFEZO on the expression levels of key regulatory proteins in HCT116 cells. RESULTS: The results demonstrated that CSENS inhibited proliferation and induced apoptosis. Apoptosis was confirmed by flow cytometry analyses, while CSENS-treated cells exhibited morphological hallmarks of apoptosis including cell shrinkage, irregularity in cellular shape, cellular detachment and chromatin condensation. Biochemical signs of apoptosis, such as DNA degradation, were observed by comet assay and gel electrophoresis. The pro-apoptotic effect of CSENS was caspase-3-independent and associated with increase of the Bax/Bcl-2 ratio. CSENS treatment down-regulated transcriptional and DNA-binding activities of NF-κB and AP-1 proteins, associated with down-regulation of their target oncogenes, c-Myc, cyclin D1 and survivin. On the other hand, CSENS up-regulated transcriptional and DNA-binding activities of Nrf2 and expression of cytoprotective genes. In addition, CSENS modulated the expression levels of ERK1/2 MAPK, p53 and p21. CONCLUSIONS: These findings suggest that CSENS may be a valuable agent for treatment of colon cancer.
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Apoptosis/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , Citoprotección/genética , FN-kappa B/antagonistas & inhibidores , Nigella sativa/metabolismo , Extractos Vegetales/farmacología , Factor de Transcripción AP-1/antagonistas & inhibidores , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ciclina D1/biosíntesis , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/biosíntesis , Roturas del ADN/efectos de los fármacos , Proteínas de Unión al ADN/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/biosíntesis , Citometría de Flujo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células HCT116 , Células Hep G2 , Humanos , Proteínas Inhibidoras de la Apoptosis/biosíntesis , Células MCF-7 , Factor 2 Relacionado con NF-E2/biosíntesis , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-myc/biosíntesis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Saponinas/farmacología , Survivin , Proteína p53 Supresora de Tumor/biosíntesis , Proteína X Asociada a bcl-2/metabolismoRESUMEN
AIM: To investigate the effects of extracts from Rhazya stricta (R. stricta) and Zingiber officinale (Z. officinale) on human colorectal cancer cells. METHODS: Human colorectal cancer cells (HCT116) were subjected to increasing doses of crude alkaloid extracts from R. stricta (CAERS) and crude flavonoid extracts from Z. officinale (CFEZO). Cells were then harvested after 24, 48 or 72 h and cell viability was examined by trypan blue exclusion dye test; clonogenicity and soft agar colony-forming assays were also carried out. Nuclear stain (Hoechst 33342), acridine orange/ethidium bromide double staining, agarose gel electrophoresis and comet assays were performed to assess pro-apoptotic potentiality of the extracts. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR), using gene-specific primers and Western blot analyses were performed to assess the impact of CAERS and CFEZO on the expression levels of key regulatory proteins in HCT116 cells. RESULTS: Treatment with a combination of CAERS and CFEZO synergistically suppressed the proliferation, colony formation and anchorage-independent growth of HCT116 cells. Calculated IC50, after 24, 48 and 72 h, were 70, 90 and 130 µg/mL for CAERS, 65, 85 and 120 µg/mL for CFEZO and 20, 25 and 45 µg/mL for both agents, respectively. CAERS- and CFEZO-treated cells exhibited morphologic and biochemical features of apoptotic cell death. The induction of apoptosis was associated with the release of mitochondrial cytochrome c, an increase in the Bax/Bcl-2 ratio, activation of caspases 3 and 9 and cleavage of poly ADP-ribose polymerase. CAERS and CFEZO treatments downregulated expression levels of anti-apoptotic proteins including Bcl-2, Bcl-X, Mcl-1, survivin and XIAP, and upregulated expression levels of proapoptotic proteins such as Bad and Noxa. CAERS and CFEZO treatments elevated expression levels of the oncosuppressor proteins, p53, p21 and p27, and reduced levels of the oncoproteins, cyclin D1, cyclin/cyclin-dependent kinase-4 and c-Myc. CONCLUSION: These data suggest that a combination of CAERS and CFEZO is a promising treatment for the prevention of colon cancer.
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Antineoplásicos Fitogénicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Apocynaceae , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales/patología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Extractos Vegetales/farmacología , Zingiber officinale , Antineoplásicos Fitogénicos/aislamiento & purificación , Apocynaceae/química , Supervivencia Celular/efectos de los fármacos , Neoplasias Colorrectales/genética , Relación Dosis-Respuesta a Droga , Zingiber officinale/química , Células HCT116 , Humanos , Concentración 50 Inhibidora , Fitoterapia , Extractos Vegetales/aislamiento & purificación , Hojas de la Planta , Plantas Medicinales , Rizoma , Transducción de Señal/efectos de los fármacos , Factores de TiempoRESUMEN
Hitherto, limited clinical impact has been achieved in the treatment of glioblastoma (GBMs). Although phytochemicals found in medicinal herbs can provide mankind with new therapeutic remedies, single agent intervention has failed to bring the expected outcome in clinical trials. Therefore, combinations of several agents at once are gaining increasing attractiveness. In the present study, we investigated the effects of crude alkaloid (CAERS) and flavonoid (CFEZO) extracts prepared from medicinal herbs, Rhazya stricta and Zingiber officinale, respectively, on the growth of human GBM cell line, U251. R. stricta and Z. officinale are traditionally used in folkloric medicine and have antioxidant, anticarcinogenic, and free radical scavenging properties. Combination of CAERS and CFEZO treatments synergistically suppressed proliferation and colony formation and effectively induced morphological and biochemical features of apoptosis in U251 cells. Apoptosis induction was mediated by release of mitochondrial cytochrome c, increased Bax : Bcl-2 ratio, enhanced activities of caspase-3 and -9, and PARP-1 cleavage. CAERS and CFEZO treatments decreased expression levels of nuclear NF-κBp65, survivin, XIAP, and cyclin D1 and increased expression level of p53, p21, and Noxa. These results suggest that combination of CAERS and CFEZO provides a useful foundation for studying and developing novel chemotherapeutic agents for the treatment of GBM.
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Antineoplásicos Fitogénicos/farmacología , Apocynaceae/química , Neoplasias Encefálicas , Proliferación Celular/efectos de los fármacos , Extractos Vegetales/farmacología , Plantas Medicinales/química , Zingiber officinale/química , Antineoplásicos Fitogénicos/química , Apoptosis/efectos de los fármacos , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células HeLa , Humanos , Proteínas de Neoplasias , Extractos Vegetales/químicaRESUMEN
There is an urgent need to improve the clinical management of non-small cell lung cancer (NSCLC), one of the most frequent causes of cancer-related deaths in men and women worldwide. Rhazya stricta, an important medicinal plant used in traditional Oriental medicine, possesses anti-oxidant, anti-carcinogenic and free radical scavenging properties. This study was done to explore the potential anticancer activity of a crude alkaloid extract of R. stricta (CAERS) against the NSCLC line A549. CAERS markedly suppressed the growth of A549 cells and considerably enhanced the anti-proliferative potential of cisplatin. CAERS-mediated inhibition of A549 cell growth correlated with the induction of apoptosis that was accompanied by numerous morphological changes, DNA fragmentation, an increase in the Bax/Bcl-2 ratio, the release of mitochondrial cytochrome c, activation of caspases 3 and 9 and cleavage of poly(ADP-ribose)-polymerase. CAERS reduced the constitutive expression of anti-apoptotic proteins (Bcl-2, Bcl-XL, Mcl-1 and Survivin) and cell cycle regulating proteins (cyclin D1 and c-Myc), but enhanced expression of the proapoptotic proteins Noxa and BAD. These observations indicate that CAERS induced apoptosis and sensitized NSCLC to cisplatin via a mitochondria-mediated apoptotic pathway. These data provide a rationale for using a combination of CAERS and CDDP to treat NSCLC and other CDDP-resistant tumors.
RESUMEN
The present study aimed to examine the antiproliferative potentiality of an extract derived from the medicinal plant ginger (Zingiber officinale) on growth of breast cancer cells. Ginger treatment suppressed the proliferation and colony formation in breast cancer cell lines, MCF-7 and MDA-MB-231. Meanwhile, it did not significantly affect viability of nontumorigenic normal mammary epithelial cell line (MCF-10A). Treatment of MCF-7 and MDA-MB-231 with ginger resulted in sequences of events marked by apoptosis, accompanied by loss of cell viability, chromatin condensation, DNA fragmentation, activation of caspase 3, and cleavage of poly(ADP-ribose) polymerase. At the molecular level, the apoptotic cell death mediated by ginger could be attributed in part to upregulation of Bax and downregulation of Bcl-2 proteins. Ginger treatment downregulated expression of prosurvival genes, such as NF-κB, Bcl-X, Mcl-1, and Survivin, and cell cycle-regulating proteins, including cyclin D1 and cyclin-dependent kinase-4 (CDK-4). On the other hand, it increased expression of CDK inhibitor, p21. It also inhibited the expression of the two prominent molecular targets of cancer, c-Myc and the human telomerase reverse transcriptase (hTERT). These findings suggested that the ginger may be a promising candidate for the treatment of breast carcinomas.