RESUMEN
The natural product 2,4ditertbutylphenol (DTBP) has a wide spectrum of biological functions, including anticancer activities, although the underlying mechanisms are poorly understood. Here, we found that DTBP induces senescence in human gastric adenocarcinoma AGS cells as evidenced by upregulation of p21 and Rb and increased ßgalactosidase activity. DTBP also induces mitotic catastrophe and generates multinucleated cells, which is accompanied by an increase in the proportion of polymerized tubulin, possibly caused by inhibition of HDAC6 enzyme activity. In silico docking analysis showed that DTBP docked at the entrance of the ligand-binding pocket of the HDAC6 enzyme. Accordingly, DTBP represents a promising lead structure for the development of HDAC6 inhibitors, with an improvement in specificity conferred by modification of the cap group. We propose for the first time that the underlying mechanism of the anticancer activity of DTBP is attributed to inhibition of HDAC6 activity.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Histona Desacetilasa 6/genética , Inhibidores de Histona Desacetilasas/administración & dosificación , Fenoles/administración & dosificación , Neoplasias Gástricas/tratamiento farmacológico , Acetilación , Adenocarcinoma/química , Adenocarcinoma/genética , Línea Celular Tumoral , Senescencia Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Histona Desacetilasa 6/antagonistas & inhibidores , Humanos , Mitosis/efectos de los fármacos , Simulación del Acoplamiento Molecular , Fenoles/química , Unión Proteica , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Tubulina (Proteína)/genéticaRESUMEN
Acquired drug resistance constitutes an enormous hurdle in cancer treatment, and the search for effective compounds against resistant cancer is still advancing. Marine organisms are a promising natural resource for the discovery and development of anticancer agents. In this study, we examined whether gliotoxin (GTX), a secondary metabolite isolated from marine-derived Aspergillus fumigatus, inhibits the growth of adriamycin (ADR)-resistant non-small-cell lung cancer (NSCLC) cell lines A549/ADR. We investigated the effects of GTX on A549/ADR cell viability with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and the induction of apoptosis in A549/ADR cells treated with GTX via fluorescence-activated cell sorting analysis, Hoechst staining, annexin V/propidium iodide staining, tetraethylbenzimidazolylcarbocyanine iodide (JC-1) staining, and western blotting. We found that GTX induced apoptosis in A549/ADR cells through the mitochondria-dependent pathway by disrupting mitochondrial membrane potential and activating p53, thereby increasing the expression levels of p21, p53 upregulated modulator of apoptosis (PUMA), Bax, cleaved poly (ADP-ribose) polymerase (PARP), and cleaved caspase-9. More importantly, we discovered that GTX works in conjunction with ADR to exert combinational effects on A549/ADR cells. In conclusion, our results suggest that GTX may have promising effects on ADR-resistant NSCLC cells by inducing mitochondria-dependent apoptosis and through the combined effects of sequential treatment with ADR.
Asunto(s)
Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Doxorrubicina/farmacología , Gliotoxina/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Células A549 , Antineoplásicos/administración & dosificación , Ciclo Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/administración & dosificación , Resistencia a Antineoplásicos , Gliotoxina/administración & dosificación , Humanos , Membranas Mitocondriales/efectos de los fármacosRESUMEN
Camphor ((1R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one), a bicyclic monoterpene, is one of the major constituents of essential oils from various herbs such as rosemary, lavender, and sage. In this study, we investigated the beneficial effects of camphor as a botanical ingredient in cosmetics. Camphor induced the proliferation of human primary dermal fibroblasts in a dose-dependent manner via the PI3K/AKT and ERK signaling pathways. Camphor attenuated the elevation of senescence associated with ß-galactosidase (SA-ß-gal) activity. Elastase activity decreased, while the total amount of collagen increased, in a dose- and time-dependent manner in human primary dermal fibroblasts treated with camphor. Camphor induced the expression of collagen IA, collagen IIIA, collagen IVA, and elastin in human primary dermal fibroblasts. In addition, posttreatment with 26 and 52 mM camphor for 2 weeks led to a significant reduction in the expression of MMP1 but increases in the expression of collagen IA, IIIA, and elastin in mouse skin exposed to UV for 4 weeks. These posttreatments also reduced the depths of the epidermis and subcutaneous fat layer in UV-exposed mouse skin. Taken together, these findings suggest camphor to be a potent wound healing and antiwrinkle agent with considerable potential for use in cosmeceuticals.
Asunto(s)
Alcanfor/farmacología , Senescencia Celular/efectos de los fármacos , Fibroblastos/efectos de los fármacos , Envejecimiento de la Piel/efectos de los fármacos , Animales , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Niño , Colágeno/metabolismo , Elastina/metabolismo , Humanos , Masculino , Matricaria/química , Metaloproteinasa 13 de la Matriz/metabolismo , Ratones , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Piel/efectos de los fármacos , Piel/efectos de la radiación , Envejecimiento de la Piel/efectos de la radiación , Rayos Ultravioleta/efectos adversos , beta-Galactosidasa/metabolismoRESUMEN
Accumulating evidence has displayed that targeting cancer stem cells (CSCs) is a very promising way for anti-cancer therapies. 2',3'-Dimethoxyflavanone (2',3'-DMF) showed the most potent toxicity of a group of 42 flavonoids tested in MCF-7-SC breast cancer stem cells. 2',3'-DMF triggered intrinsic and extrinsic apoptosis by stimulating the cleavage of PARP and the activation of caspase-9, -8, and -3. Interestingly, 2',3'-DMF induces a dramatic increase in the conversion of LC3, a well-known marker for autophagy. However, acidic vesicular organelles (AVOs), one of the autophagic flux markers were not detected. Co-treatment with chloroquine, the lysosomal inhibitor that blocks autophagic degradation did not show any change in the degree of LC3 conversion, implying that LC3 could play a role in the non-autophagic cell death of MCF-7-SC. We found that 2',3'-DMF induces the ubiquitination of caspase-8, this resulted in an interaction between caspase-8 and LC3, which led to the aggregation and activation of caspase-8. Co-treating cells with 2',3'-DMF and 3-methyladenine, an inhibitor of LC3 lipidation, reduced the activation of caspase-8. These findings provide novel insights into the anti-cancer effects of 2',3'-DMF in breast cancer stem cells by revealing that it induced apoptosis in accompany with the activation of caspase-8 mediated by LC3 conversion.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis , Caspasa 8/metabolismo , Flavanonas/farmacología , Proteínas Asociadas a Microtúbulos/metabolismo , Células Madre Neoplásicas/citología , Autofagia , Neoplasias de la Mama/metabolismo , Adhesión Celular , Daño del ADN , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Flavonas/química , Regulación Neoplásica de la Expresión Génica , Humanos , Células MCF-7 , Ubiquitina/química , UbiquitinaciónRESUMEN
The purpose of this study is to report the clinical application of Hominis Placenta Pharmacopunture for Alopecia areata. Patient was diagnosed as stress-induced Alopecia areata 1 years ago. To reduce symptom, we treated a patient 8 times using Hominis Placenta Pharmacopunture. Hominis Placenta was injected subcutaneously into the lesion of head scalp alopecia. According to photographs, the lesion had been replaced with new terminal hair and the size of the lesion had decreased. This case has shown that stress-induced Alopecia areata patient could be treated by Hominis Placenta Pharmacopunture.
RESUMEN
Epithelial-mesenchymal transition (EMT) is a critical step in the acquisition of the migratory and invasive capabilities associated with metastatic competence. Cysteine-rich protein 61 (CCN1/Cyr61) has been implicated as an important mediator in the proliferation and metastasis of breast cancer. Hence, Cyr61 and associated pathways are attractive targets for therapeutic interventions directed against the EMT. In the present study, we report that baicalein significantly inhibits the expression of Cyr61 and migration and invasion of MDA-MB231 human breast cancer cells. Exposure to baicalein led to increased E-cadherin expression, possibly due to the ubiquitination of Snail and Slug, which was mediated by the Cyr61/Akt/glycogen synthase kinase 3ß (GSK3ß) pathway. Further analysis revealed that baicalein inhibited the expression of lysyl oxidase like-2 (LOXL-2), which is a functional collaborator of Snail and Slug, and subsequently attenuated the direct interaction between LOXL-2 and Snail or Slug, thereby enhancing GSK3ß-dependent Snail and Slug degradation. Our findings provide new insights into the antimetastatic mechanism of baicalein and may contribute to its beneficial use in breast cancer therapies.
Asunto(s)
Aminoácido Oxidorreductasas/metabolismo , Proteína 61 Rica en Cisteína/antagonistas & inhibidores , Transición Epitelial-Mesenquimal/efectos de los fármacos , Flavanonas/farmacología , Antígenos CD , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Cadherinas/biosíntesis , Línea Celular Tumoral , Proteína 61 Rica en Cisteína/biosíntesis , Proteína 61 Rica en Cisteína/genética , Proteína 61 Rica en Cisteína/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Células MCF-7 , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND AND PURPOSE: Chemotherapy resistance is a major obstacle for the effective treatment of cancers. Although several studies have described the anticancer properties of rosemary extract and its components, the detailed mechanisms of action are poorly understood. METHODS: Activity-guided fractionation and repeated chromatographic separation of the n-hexane fraction of the aqueous methanol extract over silica gel, RP C18, and Sephadex LH-20 led to the isolation of three compounds. The structures of the compounds were determined using 1H, 13C, and two-dimensional nuclear magnetic resonance spectroscopy, mass spectroscopy, and infrared spectroscopy. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay was used to evaluate the cytotoxicity of these compounds. Cell cycle, apoptotic cell populations, and mitochondrial membrane potential were analyzed by flow cytometry. Western blot analysis was conducted to detect apoptosis-related proteins. RESULTS: An abietane diterpenoid, sageone (1), an icetexane diterpenoid, (-)-barbatusol (2), and a monoterpene, (+)-verbenone (3), were identified. Of these compounds, sageone (1) showed cytotoxicity against SNU-1 cells with an IC50 of 9.45 ± 1.33 µM. Sageone reduced the expression of Akt dramatically, as opposed to cisplatin, which increased phosphorylated Akt. Sageone combined with a subtoxic dose of cisplatin had synergistic effects on apoptosis induction in SNU-1 cells, as confirmed by calculating the combination index. Co-treatment was significantly more effective than monotherapy at reducing cell viability and inducing apoptosis, as determined by analyzing DNA fragmentation. The combined treatment of sageone and cisplatin markedly reduced Akt expression and phosphorylation, accompanied by increases in cleaved caspase-3, -9 and PARP. CONCLUSION: This is the first time compounds 1 and 2 have been isolated from R. officinalis. Sageone induced apoptosis in SNU-1 human gastric cancer cells and notably enhanced the cytotoxicity of cisplatin in SNU-1 cells, which are known to be resistant to cisplatin. These findings suggest that sageone represents a promising anticancer agent against gastric cancer that warrants further study.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Diterpenos/farmacología , Rosmarinus/química , Neoplasias Gástricas/tratamiento farmacológico , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Cisplatino/administración & dosificación , Cisplatino/farmacología , Diterpenos/aislamiento & purificación , Ensayos de Selección de Medicamentos Antitumorales , Hexanos/química , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Estructura Molecular , Neoplasias Gástricas/patologíaRESUMEN
Current chemotherapy is limited by the nature of invasive cancer cells, which are similar to cancer stem cells. Nanomaterials provide a potential alternate mode of cancer therapy. This study investigated the cytotoxicity of molybdenum trioxide (MoO3) nanoplates toward invasive breast cancer iMCF-7 cells by analyzing morphological changes and performing Western blot and flow cytometry analyses. The findings suggested that MoO3 exposure induces apoptosis and generates reactive oxygen species (ROS) in iMCF-7 cells. This study revealed the potential utility of MoO3 for treating metastatic cancer cells, which might enable advancements in cancer therapy.