RESUMEN
Tumor necrosis factorαmediated (TNFα) epithelialmesenchymal transition (EMT) is associated with distant metastasis in patients with colorectal cancer with poor prognosis. Although traditional herbal medicines have long been used to treat colorectal cancer, the incidence and mortality in patients with colorectal cancer has continued to increase. DangguiSayukGaOsuyuSaenggangTang (DSGOST) has long been used for treatment of chills, while few studies have reported its anticancer effect. This study aimed to demonstrate the inhibitory effect of DSGOST on TNFαmediated invasion and migration of colorectal cancer HCT116 cell lines. MTT was used to measure cell viability. Wound healing and Τranswell invasion assay were used to detect migration and invasion of cells, respectively. The intracellular localization of proteins of interest was assessed by immunocytochemistry. Western blotting was performed to determine the expression level of various proteins. A nontoxic dose of DSGOST (50 µg/ml) on HCT116 cells was determined by MTT assay. Furthermore, DSGOST prevented the TNFαinduced invasive phenotype in HCT116 cells. DSGOST inhibition of the invasive phenotype was also associated with increased expression of EMT markers. Furthermore, DSGOST treatment blocked TNFαinduced migration and invasion of HCT116 cells. In addition, DSGOST treatment inhibited TNFαmediated nuclear translocation of Snail. DSGOST treatment also downregulated TNFαinduced phosphorylation of AKT and glycogen synthase kinase3ß. Therefore, the findings of the current study suggest that DSGOST exhibits antimigration and antiinvasion effects in TNFαtreated HCT116 human colorectal cells.
Asunto(s)
Neoplasias Colorrectales/tratamiento farmacológico , Medicamentos Herbarios Chinos/administración & dosificación , Factor de Necrosis Tumoral alfa/genética , Movimiento Celular/efectos de los fármacos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Medicamentos Herbarios Chinos/química , Transición Epitelial-Mesenquimal/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glucógeno Sintasa Quinasa 3 beta/genética , Células HCT116 , Humanos , Invasividad Neoplásica/genética , Proteínas Proto-Oncogénicas c-akt/genética , Factor de Necrosis Tumoral alfa/administración & dosificaciónRESUMEN
Drug markets revisits herbal medicines, as historical usages address their therapeutic efficacies with less adverse effects. Moreover, herbal medicines save both cost and time in development. SH003, a modified version of traditional herbal medicine extracted from Astragalus membranaceus (Am), Angelica gigas (Ag), and Trichosanthes Kirilowii Maximowicz (Tk) with 1:1:1 ratio (w/w) has been revealed to inhibit tumor growth and metastasis on highly metastatic breast cancer cells, both in vivo and in vitro with no toxicity. Meanwhile, autophagy is imperative for maintenance cellular homeostasis, thereby playing critical roles in cancer progression. Inhibition of autophagy by pharmacological agents induces apoptotic cell death in cancer cells, resulting in cancer treatment. In this study, we demonstrate that SH003-induced autophagy via inhibiting STAT3 and mTOR results in an induction of lysosomal p62/SQSTM1 accumulation-mediated reactive oxygen species (ROS) generation and attenuates tumor growth. SH003 induced autophagosome and autolysosome formation by inhibiting activation of STAT3- and mTOR-mediated signaling pathways. However, SH003 blocked autophagy-mediated p62/SQSTM1 degradation through reducing of lysosomal proteases, Cathepsins, resulting in accumulation of p62/SQSTM1 in the lysosome. The accumulation of p62/SQSTM1 caused the increase of ROS, which resulted in the induction of apoptotic cell death. Therefore, we conclude that SH003 suppresses breast cancer growth by inducing autophagy. In addition, SH003-induced p62/SQSTM1 could function as an important mediator for ROS generation-dependent cell death suggesting that SH003 may be useful for treating breast cancer.
RESUMEN
Cervical cancer is a prevalent disease that may lead to mortality in women. In spite of the development of common therapeutic agents to treat cancer, there are several limitations of their use owing to side effects and drug resistance, which may induce cancer recurrence. The anticancer effects of the new herbal mixture SH003 (comprising Astragalus membranaceus, Angelica gigas and Trichosanthes kirilowii Maximowicz) have been examined in various types of cancer. Thus, the present study hypothesized that SH003 may be an effective treatment for cervical cancer. SH003 treatment inhibited the growth of HeLa cells, whereas it did not affect the growth of rat intestinal epithelial cells. In addition, SH003 treatment increased the expression of apoptosisrelated proteins and promoted apoptotic cell death in HeLa cells. SH003 treatment also led to G1 phase arrest in HeLa cells. Furthermore, SH003 treatment induced the production of reactive oxygen species (ROS); however, ROS production did not appear to be related to SH003mediated apoptosis. Results from the present study indicated that the SH003induced inhibition of HeLa cell growth may be mediated through G1 phase arrest and extrinsic apoptosis, suggested that SH003 may be a potential treatment for cervical cancer.
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Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Extractos Vegetales/farmacología , Angelica , Planta del Astrágalo , Biomarcadores , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Femenino , Células HeLa , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Trichosanthes , Neoplasias del Cuello UterinoRESUMEN
BACKGROUND: Herbal medicines have been used in cancer treatment, with many exhibiting favorable side effect and toxicity profiles compared with conventional chemotherapeutic agents. SH003 is a novel extract from Astragalus membranaceus, Angelica gigas, and Trichosanthes Kirilowii Maximowicz combined at a 1:1:1 ratio that impairs the growth of breast cancer cells. This study investigates anti-cancer effects of SH003 in prostate cancer cells. METHODS: SH003 extract in 30% ethanol was used to treat the prostate cancer cell lines DU145, LNCaP, and PC-3. Cell viability was determined by MTT and BrdU incorporation assays. Next, apoptotic cell death was determined by Annexin V and 7-AAD double staining methods. Western blotting was conducted to measure protein expression levels of components of cell death and signaling pathways. Intracellular reactive oxygen species (ROS) levels were measured using H2DCF-DA. Plasmid-mediated ERK2 overexpression in DU145 cells was used to examine the effect of rescuing ERK2 function. Results were analyzed using the Student's t-test and P-values < 0.05 were considered to indicate statistically-significant differences. RESULTS: Our data demonstrate that SH003 induced apoptosis in DU145 prostate cancer cells by inhibiting ERK signaling. SH003 induced apoptosis of prostate cancer cells in dose-dependent manner, which was independent of androgen dependency. SH003 also increased intracellular ROS levels but this is not associated with its pro-apoptotic effects. SH003 inhibited phosphorylation of Ras/Raf1/MEK/ERK/p90RSK in androgen-independent DU145 cells, but not androgen-dependent LNCaP and PC-3 cells. Moreover, ERK2 overexpression rescued SH003-induced apoptosis in DU145 cells. CONCLUSIONS: SH003 induces apoptotic cell death of DU145 prostate cancer cells by inhibiting ERK2-mediated signaling.
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Apoptosis/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Extractos Vegetales/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Angelica , Planta del Astrágalo , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Masculino , Extractos Vegetales/farmacología , TrichosanthesRESUMEN
Triple-negative breast cancer (TNBC) is a breast cancer subtype that has an aggressive phenotype, is highly metastatic, has limited treatment options and is associated with a poor prognosis. In addition, metastatic TNBC has no preferred standard chemotherapy due to resistance to anthracyclines and taxanes. The present study demonstrated that a herbal extract, SH003, reduced cell viability and induced apoptosis in TNBC without cell cytotoxicity. Cell viability was examined using trypan blue exclusion and colony formation assays, which revealed a decrease in the cell viability. Additionally, apoptosis was determined using flow cytometry and a subG1 assay, which revealed an increase in the proportion of cells in the subG1 phase. The present study investigated the anticancer effect of SH003 in the Hs578T, MDAMB231 and ZR751 TNBC cell lines, and in the MCF7 and T47D nonTNBC cell lines. Western blot analysis revealed that the expression levels of polyADPribose polymerase (PARP) cleavage protein in cells treated with SH003 were increased dosedependent manner, indicating that SH003 induced apoptosis via a caspasedependent pathway. Pretreatment with the caspase inhibitor ZVAD reduced SH003induced apoptosis was examined using trypan blue exclusion. Moreover, SH003 treatment enhanced the p73 levels in MDAMB231 cells but not in MCF7 cells. Transfection of p73 small interfering RNA (siRNA) in MDAMB0231 cells revealed that the apoptotic cell death induced by SH003 was significantly impaired in comparison with scramble siRNA transfected MDAMB231 cells. This was examined using trypan blue exclusion and flow cytometry analysis (subG1). In addition, SH003 and paclitaxel exhibited synergistic anticancer effects on TNBC cells. The results indicate that SH003 exerts its anticancer effect via p73 protein induction and exhibits synergistic anticancer effects when combined with paclitaxel.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Extractos Vegetales/farmacología , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Proteína Tumoral p73/metabolismo , Angelica , Planta del Astrágalo , Mama/efectos de los fármacos , Mama/metabolismo , Mama/patología , Caspasas/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Humanos , Paclitaxel/farmacología , Trichosanthes , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
Triple-negative breast cancer (TNBC) is highly aggressive, resulting in poor prognosis. Chemotherapy of TNBC relies on anti-cancer agents with strong cytotoxicity, but it causes several side effects with recurrence. While combinational approaches of chemotherapeutics have been highlighted as a new treatment strategy for TNBC to reduce side effects, combinations of anti-cancer agents with herbal medicines have not been reported. We recently reported that newly modified traditional Chinese medicine named SH003 inhibited TNBC growth. Considering a combinational strategy for TNBC treatment, we further studied synergistic effects of SH003 with various anti-cancer drugs in TNBC treatment. Here, we demonstrate that SH003 shows a synergistic effect with doxorubicin on TNBC treatment. Our in vitro cell viability assays revealed that SH003 and doxorubicin showed a synergistic effect in the well-defined TNBC cell line, MDA-MB-231. Moreover, we found that the combinational treatment caused Caspase-dependent apoptotic cell death. Our in vivo mouse xenograft tumor growth assays confirmed that combinational treatment of SH003 with doxorubicin repressed MDA-MB-231 tumor growth with no weight loss. Therefore, we conclude that the combinational treatment of SH003 with doxorubicin shows the synergism in TNBC treatment, and suggest that SH003 can be used together with conventional anti-cancer drugs in chemotherapeutic approaches. Copyright © 2016 John Wiley & Sons, Ltd.
Asunto(s)
Antineoplásicos/uso terapéutico , Doxorrubicina/uso terapéutico , Extractos Vegetales/uso terapéutico , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Angelica , Animales , Antineoplásicos/farmacología , Apoptosis , Planta del Astrágalo , Línea Celular Tumoral , Doxorrubicina/farmacología , Sinergismo Farmacológico , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Extractos Vegetales/farmacología , Trichosanthes , Neoplasias de la Mama Triple Negativas/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Tumor angiogenesis is a key feature of cancer progression, because a tumor requires abundant oxygen and nutrition to grow. Here, we demonstrate that SH003, a mixed herbal extract containing Astragalus membranaceus (Am), Angelica gigas (Ag) and Trichosanthes Kirilowii Maximowicz (Tk), represses VEGF-induced tumor angiogenesis both in vitro and in vivo. SH003 inhibited VEGF-induced migration, invasion and tube formation in human umbilical vein endothelial cells (HUVEC) with no effect on the proliferation. SH003 reduced CD31-positive vessel numbers in tumor tissues and retarded tumor growth in our xenograft mouse tumor model, while SH003 did not affect pancreatic tumor cell viability. Consistently, SH003 inhibited VEGF-stimulated vascular permeability in ears and back skins. Moreover, SH003 inhibited VEGF-induced VEGFR2-dependent signaling by blocking VEGF binding to VEGFR2. Therefore, our data conclude that SH003 represses tumor angiogenesis by inhibiting VEGF-induced VEGFR2 activation, and suggest that SH003 may be useful for treating cancer.
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Neovascularización Patológica/tratamiento farmacológico , Neoplasias Pancreáticas/irrigación sanguínea , Neoplasias Pancreáticas/tratamiento farmacológico , Extractos Vegetales/farmacología , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Angelica , Animales , Planta del Astrágalo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Neoplasias Pancreáticas/patología , Distribución Aleatoria , Transducción de Señal , Trichosanthes , Factor A de Crecimiento Endotelial Vascular/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Rhus verniciflua Stokes (RVS) belongs to the Anacardiaceae family and traditionally used for cancer treatment. RVS and butein, a major compound of RVS, were known to induce apoptosis via AKT inhibition in cancer cells. Thus, in this study, we investigated the effect of RVS and its derivative compounds (fisetin, quercetin, butein) on cell death in SKOV-3/PAX cells. METHODS: The 80 % ethanol extract of RVS and its derivative compounds (fisetin, quercetin, butein) were prepared. The cytotoxicity was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay. Apoptotic cells were detected by staining with propidium iodide (PI) and Annexin V-fluorescein isothiocyanate/7-aminoactinomycin D (Annexin V-FITC/7-AAD). The expression level of intracellular signaling related-proteins in apoptosis and growth were measured by western blot assay. RESULTS: We found that RVS and butein suppressed the growth of SKOV-3/PAX cells in a dose-dependent manner. We also found that RVS and butein produced the cleavage of caspase-9, -8, -3, and PARP. Similarly, sub-G1 phase and Annexin V-FITC positive cells were increased by RVS and butein. Moreover, RVS and butein significantly reduced AKT phosphorylation in SKOV-3/PAX cells. PI3K inhibitor LY294002 caused PARP cleavage supporting our finding. CONCLUSION: Our data clearly indicate that RVS and butein induce apoptosis of SKOV-3/PAX cells through inhibition of AKT activation. RVS and butein could be useful compounds for the treatment for paclitaxel resistant-ovarian cancer.
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Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Neoplasias Ováricas/tratamiento farmacológico , Paclitaxel/farmacología , Extractos Vegetales/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Rhus/química , Línea Celular Tumoral , Chalconas/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Humanos , FosforilaciónRESUMEN
Despite its therapeutic advantages, chemotherapy can also cause adverse effects, including anorexia and loss of appetite. Although numerous patients with cancer have been reported to suffer from anorexia during or following chemotherapy, treatment options for anorexia remain to be determined. In Asian countries, traditional medicines are widely used to treat problems with appetite; sip-jeon-dea-bo-tang (SJDBT) is one of those medicines used for the treatment of anorexia. The present study demonstrated that SJDBT ameliorated cisplatin-induced anorexia. In a mouse model of chemotherapy-induced anorexia, oral administration of SJDBT prevented the cisplatin-induced reduction of food intake, inhibiting weight loss. The results of multiplex assays showed that SJDBT only altered the levels of interleukin (IL)-6 and leptin in the serum and fat tissue. In addition, SJDBT maintained the serum leptin level and increased the serum IL-6 level, whereas cisplatin reduced the levels of both serum leptin and IL6. Furthermore, SJDBT was revealed to increase the levels of leptin and IL-6 in the fat tissue by activating the JAK1/STAT3 signaling pathway. In conclusion, the present results revealed that SJDBT ameliorated cisplatin-induced anorexia, suggesting its usefulness in the prevention of anorexia during chemotherapy.
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Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Anorexia/metabolismo , Medicamentos Herbarios Chinos/farmacología , Interleucina-6/biosíntesis , Janus Quinasa 1/metabolismo , Leptina/biosíntesis , Factor de Transcripción STAT3/metabolismo , Animales , Anorexia/tratamiento farmacológico , Anorexia/etiología , Antineoplásicos/efectos adversos , Cisplatino/efectos adversos , Modelos Animales de Enfermedad , Masculino , Ratones , Transducción de Señal/efectos de los fármacosRESUMEN
Cancer inflammation promotes cancer progression, resulting in a high risk of cancer. Here, we demonstrate that our new herbal extract, SH003, suppresses both tumor growth and metastasis of MDA-MB-231 breast cancer cells via inhibiting STAT3-IL-6 signaling path. Our new herbal formula, SH003, mixed extract from Astragalus membranaceus, Angelica gigas, and Trichosanthes kirilowii Maximowicz, suppressed MDA-MB-231 tumor growth and lung metastasis in vivo and reduced the viability and metastatic abilities of MDA-MB-231 cells in vitro. Furthermore, SH003 inhibited STAT3 activation, which resulted in a reduction of IL-6 production. Therefore, we conclude that SH003 suppresses highly metastatic breast cancer growth and metastasis by inhibiting STAT3-IL-6 signaling path.
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Antineoplásicos Fitogénicos/farmacología , Neoplasias de la Mama/metabolismo , Interleucina-6/metabolismo , Extractos Vegetales/farmacología , Factor de Transcripción STAT3/metabolismo , Angelica/química , Astragalus propinquus/química , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Femenino , Humanos , Transducción de Señal/efectos de los fármacos , Trichosanthes/químicaRESUMEN
Cancer-associated anorexia and cachexia are a multifactorial condition described by a loss of body weight and muscle with anorexia, asthenia, and anemia. Moreover, they correlate with a high mortality rate, poor response to chemotherapy, poor performance status, and poor quality of life. Cancer cachexia is regulated by proinflammatory cytokines such as interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor- α (TNF- α). In addition, glucagon like peptide-1 (GIP-1), peptide YY (PYY), ghrelin, and leptin plays a crucial role in food intake. In this study, we investigated the therapeutic effects of one of the traditional herbal medicines, Sipjeondaebo-tang (Juzen-taiho-to in Japanese; SJDBT), on cancer anorexia and cachexia in a fundamental mouse cancer anorexia/cachexia model, CT-26 tumor-bearing mice. SJDBT was more significantly effective in a treatment model where it was treated after anorexia and cachexia than in a prevention model where it was treated before anorexia and cachexia on the basis of parameters such as weights of muscles and whole body and food intakes. Moreover, SJDBT inhibited a production of IL-6, MCP-1, PYY, and GLP-1 and ameliorated cancer-induced anemia. Therefore, our in vivo studies provide evidence on the role of SJDBT in cancer-associated anorexia and cachexia, thereby suggesting that SJDBT may be useful for treating cancer-associated anorexia and cachexia.
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Anorexia/complicaciones , Caquexia/complicaciones , Medicamentos Herbarios Chinos/farmacología , Neoplasias/complicaciones , Animales , Anorexia/tratamiento farmacológico , Peso Corporal , Caquexia/tratamiento farmacológico , Línea Celular Tumoral , Quimiocina CCL2/sangre , Ghrelina/sangre , Péptido 1 Similar al Glucagón/sangre , Inflamación , Interleucina-6/sangre , Mucosa Intestinal/metabolismo , Leptina/sangre , Masculino , Ratones , Ratones Endogámicos BALB C , Músculos/patología , Trasplante de Neoplasias , Neoplasias/tratamiento farmacológico , Péptido YY/sangre , Preparaciones de Plantas/farmacología , Factor de Necrosis Tumoral alfa/sangreRESUMEN
The objective of the present study was to analyze the effect of a mixture of medicinal plants [Angelica gigas Nakai, Panax ginseng and Rhus verniciflua Stokes (APR)] on lipopolysaccharide (LPS)-induced inflammatory responses in the murine macrophage cell line RAW264.7. Cells were treated with APR and LPS at various concentrations and indicated times. WST assay, trypan blue assay and quantification of activated cells demonstrated that APR suppressed cell proliferation in a dose-dependent manner. APR induced G1 cell cycle arrest and inhibited the LPS-induced phosphorylation of protein kinase B (AKT), extracellular signal-regulated kinase (ERK), mitogen-activated protein kinase (p38) and necrosis factor κB (NF-κB). APR also suppressed nitric oxide synthase isoform (iNOS) and prostaglandin endoperoxide synthase 2 (Cox-2) messenger ribonucleic acid (mRNA) expression induced by LPS. Furthermore, APR decreased LPS-induced intracellular reactive oxygen species (ROS) levels, mitochondrial membrane potential, as well as induced PARP and caspase-3 cleavage, suggesting that APR causes apoptosis. In conclusion, the present study indicated that APR may be advantageous in treating inflammatory disease.
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Antiinflamatorios/farmacología , Medicina de Hierbas , Macrófagos/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Regulación de la Expresión Génica/efectos de los fármacos , Macrófagos/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Extractos Vegetales/farmacología , Plantas Medicinales/química , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Inflammatory response is a major defense mechanism against pathogens and chemical or mechanical injury. Rhus verniciflua Stokes (RVS) has traditionally been used as an ingredient in East Asian medicine for the treatment of gastritis, stomach cancer and atherosclerosis. The aim of the current study was to analyze the effect of RVS on LPSinduced inflammatory responses in the RAW264.7 mouse macrophage cell line. RAW264.7 cells were treated with various concentrations of RVS and LPS at specific time points. WST assay, trypan blue assay and quantification of activated cells revealed that RVS suppressed cell proliferation in a dosedependent manner. RVS induced G1 cell cycle arrest, suppressed iNOS and COX2 mRNA expression induced by LPS and decreased intracellular ROS levels induced by LPS. In addition, RVS induced PARP and caspase3 cleavage suggesting that RVS causes cell death. Results of the present study indicate that RVS may be advantageous in treating inflammatory disease.
Asunto(s)
Antiinflamatorios/química , Extractos Vegetales/química , Rhus/química , Animales , Antiinflamatorios/farmacología , Caspasa 3/genética , Caspasa 3/metabolismo , Línea Celular , Proliferación Celular/efectos de los fármacos , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Lipopolisacáridos/farmacología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Medicina Tradicional de Asia Oriental , Ratones , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Extractos Vegetales/farmacología , Poli(ADP-Ribosa) Polimerasas/genética , Poli(ADP-Ribosa) Polimerasas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Rhus/metabolismoRESUMEN
Saussurea lappa Clarke (SLC) has been used as a traditional medicine in Korea, China, and Japan for the treatment of abdominal pain and tenesmus. Costunolide, a sesquiterpene lactone isolated from SLC, has diverse medicinal effects. However, the anticancer effects of costunolide are still unclear in breast cancer. In this study, we demonstrate that costunolide suppresses tumor growth and metastases of MDA-MB-231 highly metastatic human breast cancer cells via inhibiting TNFα-induced NF-κB activation. Costunolide inhibited MDA-MB-231 tumor growth and metastases without affecting body weights in the in vivo mouse orthotopic tumor growth assays. In addition, costunolide inhibited in vitro TNFα-induced invasion and migration of MDA-MB-231 cells. Costunolide further suppressed TNFα-induced NF-κB signaling activation, resulting in a reduced expression of MMP-9, a well-known NF-κB-dependent gene to mediate breast cancer cell growth and metastases. Therefore, we conclude that SLC and its derivative costunolide suppress breast cancer growth and metastases by inhibiting TNFα-induced NF-κB activation, suggesting that costunolide as well as SLC may be promising anticancer drugs, especially for metastatic breast cancer.
RESUMEN
Cancer cells acquire anticancer drug resistance during chemotherapy, which aggravates cancer disease. MDR1 encoded from multidrug resistance gene 1 mainly causes multidrug resistance phenotypes of different cancer cells. In this study, we demonstrate that JNK1/2 activation by an extract from the root of Morus alba L. (White mulberry) reduces doxorubicin-resistant MCF-7/Dox cell viability by inhibiting YB-1 regulation of MDR1 gene expression. When MCF-7 or MCF-7/Dox cells, where MDR1 is highly expressed were treated with an extract from roots or leaves of Morus alba L., respectively, the root extract from the mulberry (REM) but not the leaf extract (LEM) reduced cell viabilities of both MCF-7 and MCF-7/Dox cells, which was enhanced by cotreatment with doxorubicin. REM but not LEM further inhibited YB-1 nuclear translocation and its regulation of MDR1 gene expression. Moreover, REM promoted phosphorylation of c-Jun NH2-terminal kinase 1/2 (JNK1/2) and JNK1/2 inhibitor, SP600125 and rescued REM inhibition of both MDR1 expression and viabilities in MCF-7/Dox cells. Consistently, overexpression of JNK1, c-Jun, or c-Fos inhibited YB-1-dependent MDR1 expression and reduced viabilities in MCF-7/Dox cells. In conclusion, our data indicate that REM-activated JNK-cJun/c-Fos pathway decreases the viability of MCF-7/Dox cells by inhibiting YB-1-dependent MDR1 gene expression. Thus, we suggest that REM may be useful for treating multidrug-resistant cancer cells.
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Tumor-associated macrophages (TAMs) in tumor microenvironment regulate cancer progression and metastases. In breast cancer, macrophage infiltration is correlated with a poor prognosis. While metastatic breast cancer is poor prognostic with a severe mortality, therapeutic options are still limited. In this study, we demonstrate that KSG-002, a new herbal composition of radices Astragalus membranaceus and Angelica gigas, suppresses breast cancer via inhibiting TAM recruitment. KSG-002, an extract of radices Astragalus membranaceus and Angelica gigas at 3 : 1 ratio, respectively, inhibited MDA-MB-231 xenograft tumor growth and pulmonary metastasis in nude mice, while KSG-001, another composition (1 : 1 ratio, w/w), enhanced tumor growth, angiogenesis, and pulmonary metastasis, in vivo. KSG-002 further decreased the infiltrated macrophage numbers in xenograft tumor cohorts. In Raw264.7 cells, KSG-002 but not KSG-001 inhibited cell proliferation and migration and reduced TNF-alpha (TNF α ) production by inhibiting NF- κ B pathway. Furthermore, a combinatorial treatment of KSG-002 with TNF α inhibited a proliferation and migration of both MDA-MB-231 and Raw264.7 cells. Taken together, we conclude that KSG-002 suppresses breast cancer growth and metastasis through targeting NF- κ B-mediated TNF α production in macrophages.
RESUMEN
Phytoestrogens are known to prevent tumor induction. But their molecular mechanisms of action are still unknown. This study aimed to examine the effect of apigenin on proliferation and apoptosis in HER2-expressing breast cancer cells. In our experiments, apigenin inhibited the proliferation of MCF-7 vec and MCF-7 HER2 cells. This growth inhibition was accompanied with an increase of sub G(0)/G(1) apoptotic fractions. Overexpression of HER2 did not confer resistance to apigenin in MCF-7 cells. Apigenin-induced extrinsic apoptosis pathway up-regulating the levels of cleaved caspase-8, and inducing the cleavage of poly (ADP-ribose) polymerase, whereas apigenin did not induce apoptosis via intrinsic mitochondrial apoptosis pathway since this compound did not decrease mitochondrial membrane potential maintaining red fluorescence and did not affect the levels of B-cell lymphoma 2 (BCL2) and Bcl-2-associated X protein. Moreover, apigenin reduced the tyrosine phosphorylation of HER2 (phospho-HER2 level) in MCF-7 HER2 cells, and up-regulated the levels of p53, phospho-p53 and p21 in MCF-7 vec and MCF-7 HER2 cells. This suggests that apigenin induces apoptosis through p53-dependent pathway. Apigenin also reduced the expression of phospho-JAK1 and phospho-STAT3 and decreased STAT3-dependent luciferase reporter gene activity in MCF-7 vec and MCF-7 HER2 cells. Apigenin decreased the phosphorylation level of IκBα in the cytosol, and abrogated the nuclear translocation of p65 within the nucleus suggesting that it blocks the activation of NFκB signaling pathway in MCF-7 vec and MCF-7 HER2 cells. Our study indicates that apigenin could be a potential useful compound to prevent or treat HER2-overexpressing breast cancer.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Apigenina/farmacología , Apoptosis/efectos de los fármacos , Fitoestrógenos/farmacología , Receptor ErbB-2/metabolismo , Transducción de Señal/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/metabolismo , Neoplasias de la Mama , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Perfilación de la Expresión Génica , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Potencial de la Membrana Mitocondrial , FN-kappa B/metabolismo , Factor de Transcripción STAT3/metabolismo , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
KM110329 is four traditional herbal medicine mixtures with anti-inflammatory properties. Atopic dermatitis (AD) is an inflammatory skin disease associated with enhanced T-helper2 (Th2) lymphocyte response to allergens that results in elevated serum eosinophil and Immunoglobulin E (IgE) levels and leukocyte infiltration in atopic skin sites. In this study, we investigated the effect of topical application of KM110329 ethanol extract on the ovalbumin (OVA) or 2,4-dinitrochlorobenzene- (DNCB-) induced AD mouse models. For that purpose, we observed the effects of KM110329 on blood eosinophils, skin mast cells, production of serum IgE, and expression of cytokine mRNA in the atopic dermatitis skin lesions of OVA allergen- or DNCB-treated BALB/c mice. KM110329 significantly reduced blood eosinophils cell numbers in OVA or DNCB-treated BALB/c mice. Histological analyses demonstrated decreased mast cell count as well as dermal infiltration by inflammatory cells. In the skin lesions, mRNA expression of interleukine (IL)-4, IL-13, and IL-17 was inhibited by KM110329. KM110329 also suppressed the production of serum IgE level in both the OVA- and DNCB-induced atopic dermatitis model. Taken together, our results showed that topical application of KM110329 extracts exerts beneficial effects in AD symptoms, suggesting that KM110329 might be a useful candidate for the treatment of AD.
RESUMEN
BACKGROUND: Phytoestrogens are known to prevent tumor induction. But their molecular mechanisms of action are largely unknown. This study aimed to examine the effect of genistein and quercetin on proliferation and apoptosis in HER2-expressing breast cancer cells. MATERIALS AND METHODS: The antiproliferative effects of phytoestrogens were tested by proliferation assays. Flow cytometry was performed to analyze the cell cycle. The effect of phytoestrogens on cell-signaling molecules was determined by Western blotting. RESULTS: Genistein and quercetin inhibited the proliferation of MCF-7 vec and MCF-7 HER2 cells. This growth inhibition was accompanied with an increase of subG(0)/G(1) apoptotic fractions. Genistein and quercetin induced extrinsic apoptosis pathway, up-regulating p53. Genistein and quercetin reduced the phosphorylation level of IκBα, and abrogated the nuclear translocation of p65 and its phosphorylation within the nucleus. CONCLUSION: Genistein and quercetin exert their antiproliferative activity by inhibiting NFκB signaling. Phytoestrogens could be potential useful compounds to prevent or treat HER2-overexpressing breast cancer.