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1.
J Environ Pathol Toxicol Oncol ; 40(2): 65-79, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33822518

RESUMEN

Environmental pollution (EP) is a well-known threat to wild animals, but its toxicological impact is poorly understood. In vitro toxicity evaluation using cells of lower predators could be a promising way to assess and monitor the effects of EPs on whole wildlife populations that are related in the food web. Here, we describe EPs' toxic effect and mechanism in the primary fibroblast derived from the embryo of the striped field mouse, Apodemus agrarius. Characterization of the primary fibroblast was via morphology, genetics, immunocytochemistry, and stable culture conditions for optimal toxicity screening. Cell viability assays-MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and lactate dehydrogenase (LDH)-were performed to observe cytotoxicity, and quantitative PCR was conducted to confirm gene alteration by EP exposure. MTT and LDH assays confirmed the cytotoxicity of transfluthrin (TF), benzyl butyl phthalate (BBP), and 17ß-estradiol (E2) with IC50 values of 10.56 µM, 10.82 µM, and 24.08 µM, respectively, following 48-h exposures. mRNA expression of androgen-binding protein, growth hormone receptor, cytochrome C oxidase, and cytochrome P450-1A1 was induced after exposure to TF, BBP, and E2. We unveiled new EP mechanisms at the mammalian cellular level and discovered potential biomarker genes for monitoring of EPs. Based on our findings, we propose the primary fibroblast of A. agrarius as a valuable model to assess the toxicological effects of EP on wildlife.


Asunto(s)
Ciclopropanos/toxicidad , Disruptores Endocrinos/toxicidad , Estradiol/toxicidad , Estrógenos/toxicidad , Fibroblastos/efectos de los fármacos , Fluorobencenos/toxicidad , Insecticidas/toxicidad , Ácidos Ftálicos/toxicidad , Proteína de Unión a Andrógenos/genética , Animales , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Ciclooxigenasa 1/genética , Citocromo P-450 CYP1A1/genética , Embrión de Mamíferos/citología , Fibroblastos/metabolismo , Murinae , Receptores de Somatotropina/genética
2.
Int J Nanomedicine ; 16: 1993-2011, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33727811

RESUMEN

Background: Even with considerable improvement in treatment of epithelial ovarian cancer achieved in recent years, an increasing chemotherapy resistance and disease 5-year relapse is recorded for a majority part of patients that encourages the search for better therapeutic options. Gold nanoparticles (Au NPs) due to plethora of unique physiochemical features are thoroughly tested as drug delivery, radiosensitizers, as well as photothermal and photodynamic therapy agents. Importantly, due to highly controlled synthesis, it is possible to obtain nanomaterials with directed size and shape. Methods: In this work, we developed novel elongated-type gold nanoparticles in the shape of nanopeanuts (AuP NPs) and investigated their cytotoxic potential against ovarian cancer cells SKOV-3 using colorimetric and fluorimetric methods, Western blot, flow cytometry, and fluorescence microscopy. Results: Peanut-shaped gold nanoparticles showed high anti-cancer activity in vitro against SKOV-3 cells at doses of 1-5 ng/mL upon 72 hours treatment. We demonstrate that AuP NPs decrease the viability and proliferation capability of ovarian cancer cells by triggering cell apoptosis and autophagy, as evidenced by flow cytometry and Western blot analyses. The overproduction of reactive oxygen species (ROS) was noted to be a critical mediator of AuP NPs-mediated cell death. Conclusion: These data indicate that gold nanopeanuts might be developed as nanotherapeutics against ovarian cancer.


Asunto(s)
Apoptosis , Autofagia , Oro/química , Nanopartículas del Metal/química , Neoplasias Ováricas/patología , Especies Reactivas de Oxígeno/metabolismo , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/metabolismo , Arachis , Autofagia/efectos de los fármacos , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Femenino , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Nanopartículas del Metal/toxicidad , Nanopartículas del Metal/ultraestructura , Neoplasias Ováricas/tratamiento farmacológico , Oxidación-Reducción
3.
Nat Commun ; 12(1): 1773, 2021 03 19.
Artículo en Inglés | MEDLINE | ID: mdl-33741995

RESUMEN

The exploration of artificial luminogens with bright emission has been fully developed with the advancement of synthetic chemistry. However, many of them face problems like weakened emission in the aggregated state as well as poor renewability and sustainability. Therefore, the development of renewable and sustainable luminogens with anti-quenching function in the solid state, as well as to unveil the key factors that influence their luminescence behavior become highly significant. Herein, a new class of natural rosin-derived luminogens with aggregation-induced emission property (AIEgens) have been facilely obtained with good biocompatibility and targeted organelle imaging capability as well as photochromic behavior in the solid state. Mechanistic study indicates that the introduction of the alicyclic moiety helps suppress the excited-state molecular motion to enhance the solid-state emission. The current work fundamentally elucidates the role of alicyclic moiety in luminogen design and practically demonstrates a new source to large-scalely obtain biocompatible AIEgens.


Asunto(s)
Materiales Biocompatibles/química , Colorantes Fluorescentes/química , Luminiscencia , Resinas de Plantas/química , Animales , Materiales Biocompatibles/farmacología , Células COS , Supervivencia Celular/efectos de los fármacos , Chlorocebus aethiops , Escherichia coli/efectos de los fármacos , Colorantes Fluorescentes/farmacología , Microscopía Confocal , Estructura Molecular , Movimiento (Física) , Imagen Óptica/métodos , Orgánulos/química , Orgánulos/metabolismo , Resinas de Plantas/farmacología , Relación Estructura-Actividad
4.
Molecules ; 26(5)2021 Feb 24.
Artículo en Inglés | MEDLINE | ID: mdl-33668106

RESUMEN

Tagetes erecta L. is a popular ornamental plant of the Asteraceae family, which is widely cultivated not only for its decorative use, but also for the extraction of lutein. Besides carotenoid representatives, which have been extensively studied, other important classes of secondary metabolites present in the plant, such as polyphenols, could exhibit important biological activities. The phytochemical analysis of a methanolic extract obtained from T. erecta inflorescences was achieved using liquid chromatography-mass spectrometry (LC-MS) techniques. The extract was further subjected to a multistep purification process, which allowed the separation of different fractions. The total extract and its fractions contain several polyphenolic compounds, such as hydroxybenzoic and hydroxycinnamic acid derivatives, flavonols (especially quercetagetin glycosides), and several aglycons (e.g., quercetin, patuletin). One of the fractions, containing mostly quercetagitrin, was subjected to two different antioxidant assays (metal chelating activity and lipoxygenase inhibition) and to in vitro cytotoxicity assessment. Generally, the biological assays showed promising results for the investigated fraction compared to the initial extract. Given the encouraging outcome of the in vitro assays, further purification and structural analysis of compounds from T. erecta extracts, as well as further in vivo investigations are justified.


Asunto(s)
Antioxidantes/farmacología , Flores/química , Inhibidores de la Lipooxigenasa/farmacología , Fitoquímicos/farmacología , Extractos Vegetales/farmacología , Tagetes/química , Animales , Antioxidantes/química , Antioxidantes/aislamiento & purificación , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Fibroblastos/efectos de los fármacos , Lipooxigenasa/metabolismo , Inhibidores de la Lipooxigenasa/química , Inhibidores de la Lipooxigenasa/aislamiento & purificación , Fitoquímicos/química , Fitoquímicos/aislamiento & purificación , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Conejos , Relación Estructura-Actividad
5.
Chem Biol Interact ; 338: 109428, 2021 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-33647240

RESUMEN

Camostat mesylate, a potent inhibitor of the human transmembrane protease, serine 2 (TMPRSS2), is currently under investigation for its effectiveness in COVID-19 patients. For its safe application, the risks of camostat mesylate to induce pharmacokinetic drug-drug interactions with co-administered drugs should be known. We therefore tested in vitro the potential inhibition of important efflux (P-glycoprotein (P-gp, ABCB1), breast cancer resistance protein (BCRP, ABCG2)), and uptake transporters (organic anion transporting polypeptides OATP1B1, OATP1B3, OATP2B1) by camostat mesylate and its active metabolite 4-(4-guanidinobenzoyloxy)phenylacetic acid (GBPA). Transporter inhibition was evaluated using fluorescent probe substrates in transporter over-expressing cell lines and compared to the respective parental cell lines. Moreover, possible mRNA induction of pharmacokinetically relevant genes regulated by the nuclear pregnane X receptor (PXR) and aryl hydrocarbon receptor (AhR) was analysed in LS180 cells by quantitative real-time PCR. The results of our study for the first time demonstrated that camostat mesylate and GBPA do not relevantly inhibit P-gp, BCRP, OATP1B1 or OATP1B3. Only OATP2B1 was profoundly inhibited by GBPA with an IC50 of 11 µM. Induction experiments in LS180 cells excluded induction of PXR-regulated genes such as cytochrome P450 3A4 (CYP3A4) and ABCB1 and AhR-regulated genes such as CYP1A1 and CYP1A2 by camostat mesylate and GBPA. Together with the summary of product characteristics of camostat mesylate indicating no inhibition of CYP1A2, 2C9, 2C19, 2D6, and 3A4 in vitro, our data suggest a low potential of camostat mesylate to act as a perpetrator in pharmacokinetic drug-drug interactions. Only inhibition of OATP2B1 by GBPA warrants further investigation.


Asunto(s)
Interacciones Farmacológicas , Ésteres/metabolismo , Guanidinas/metabolismo , Inhibidores de Serina Proteinasa/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/antagonistas & inhibidores , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Línea Celular , Supervivencia Celular/efectos de los fármacos , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Ésteres/química , Ésteres/farmacología , Guanidinas/química , Guanidinas/farmacología , Humanos , Transportadores de Anión Orgánico/antagonistas & inhibidores , Transportadores de Anión Orgánico/metabolismo , Receptor X de Pregnano/genética , Receptor X de Pregnano/metabolismo , ARN Mensajero/metabolismo , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/metabolismo , Serina Endopeptidasas/química , Serina Endopeptidasas/metabolismo , Inhibidores de Serina Proteinasa/química , Inhibidores de Serina Proteinasa/farmacología
6.
Ecotoxicol Environ Saf ; 214: 112078, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33676053

RESUMEN

It is well known that the dairy cow production is very sensitive to environmental factors, including high temperature, high humidity and radiant heat sources. High temperature-induced heat stress is the main environmental factor that causes oxidative stress and apoptosis, which affects the development of mammary glands in dairy cows. Dihydromyricetin (DMY) is a nature flavonoid compound extracted from Ampelopsis grossedentata; it has been shown to have various pharmacological functions, such as anti-inflammation, antitumor and liver protection. The present study aims to evaluate the protective effect of DMY on heat stress-induced dairy cow mammary epithelial cells (DCMECs) apoptosis and explore the potential mechanisms. The results show that heat stress triggers heat shock response and reduces cell viability in DCMECs; pretreatment of DCMECs with DMY (25 µM) for 12 h significantly alleviates the negative effects of heat stress on cells. DMY can provide cytoprotective effects by suppressing heat stress-caused mitochondrial membrane depolarization and mitochondrial dysfunction, Bax and Caspase 3 activity, and modulation of oxidative enzymes, thereby preventing ROS production and apoptosis in DCMECs. Importantly, DMY treatment could attenuate heat stress-induced mitochondrial fragmentation through mediating the expression of mitochondrial fission and fusion-related genes, including Dynamin related protein 1 (Drp1), Mitochondrial fission 1 protein (Fis1), and Mitofusin1, 2 (Mfn1, 2). Above all, our findings demonstrate that DMY could protect DCMECs against heat stress-induced injury through preventing oxidative stress, the imbalance of mitochondrial fission and fusion, which provides useful evidence that DMY can be a promising therapeutic drug for protecting heat stress-induced mammary glands injury and mastitis.


Asunto(s)
Flavonoles/farmacología , Respuesta al Choque Térmico/efectos de los fármacos , Sustancias Protectoras/farmacología , Animales , Apoptosis/efectos de los fármacos , Bovinos , Supervivencia Celular/efectos de los fármacos , Dinaminas , Células Epiteliales/efectos de los fármacos , Femenino , Mitocondrias/efectos de los fármacos , Dinámicas Mitocondriales/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos
7.
Molecules ; 26(5)2021 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-33652694

RESUMEN

Colorectal cancer (CRC) is the third most common type of cancer worldwide and a leading cause of cancer death. According to the Malaysian National Cancer Registry Report 2012-2016, colorectal cancer was the second most common cancer in Malaysia after breast cancer. Recent treatments for colon cancer cases have caused side effects and recurrence in patients. One of the alternative ways to fight cancer is by using natural products. Curcumin is a compound of the rhizomes of Curcuma longa that possesses a broad range of pharmacological activities. Curcumin has been studied for decades but due to its low bioavailability, its usage as a therapeutic agent has been compromised. This has led to the development of a chemically synthesized curcuminoid analogue, (2E,6E)-2,6-bis(2,3-dimethoxybenzylidine) cyclohexanone (DMCH), to overcome the drawbacks. This study aims to examine the potential of DMCH for cytotoxicity, apoptosis induction, and activation of apoptosis-related proteins on the colon cancer cell lines HT29 and SW620. The cytotoxic activity of DMCH was evaluated using the [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] (MTT) cell viability assay on both of the cell lines, HT29 and SW620. To determine the mode of cell death, an acridine orange/propidium iodide (AO/PI) assay was conducted, followed by Annexin V/FITC, cell cycle analysis, and JC-1 assay using a flow cytometer. A proteome profiler angiogenesis assay was conducted to determine the protein expression. The inhibitory concentration (IC50) of DMCH in SW620 and HT29 was 7.50 ± 1.19 and 9.80 ± 0.55 µg/mL, respectively. The treated cells displayed morphological features characteristic of apoptosis. The flow cytometry analysis confirmed that DMCH induced apoptosis as shown by an increase in the sub-G0/G1 population and an increase in the early apoptosis and late apoptosis populations compared with untreated cells. A higher number of apoptotic cells were observed on treated SW620 cells as compared to HT29 cells. Human apoptosis proteome profiler analysis revealed upregulation of Bax and Bad proteins and downregulation of Livin proteins in both the HT29 and SW620 cell lines. Collectively, DMCH induced cell death via apoptosis, and the effect was more pronounced on SW620 metastatic colon cancer cells, suggesting its potential effects as an antimetastatic agent targeting colon cancer cells.


Asunto(s)
Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , Curcumina/farmacología , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/genética , Supervivencia Celular/efectos de los fármacos , Neoplasias del Colon/patología , Curcuma/química , Curcumina/análogos & derivados , Curcumina/química , Diarilheptanoides/química , Diarilheptanoides/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células HT29 , Humanos , Extractos Vegetales/química , Extractos Vegetales/farmacología
8.
Molecules ; 26(5)2021 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-33652957

RESUMEN

Multidrug resistance (MDR) remains a major problem in cancer therapy and is characterized by the overexpression of p-glycoprotein (P-gp) efflux pump, upregulation of anti-apoptotic proteins or downregulation of pro-apoptotic proteins. In this study, an Apolipoprotein A1 (ApoA1)-modified cationic liposome containing a synthetic cationic lipid and cholesterol was developed for the delivery of a small-molecule chemotherapeutic drug, doxorubicin (Dox) to treat MDR tumor. The liposome-modified by ApoA1 was found to promote drug uptake and elicit better therapeutic effects than free Dox and liposome in MCF-7/ADR cells. Further, loading Dox into the present ApoA1-liposome systems enabled a burst release at the tumor location, resulting in enhanced anti-tumor effects and reduced off-target effects. More importantly, ApoA1-lip/Dox caused fewer adverse effects on cardiac function and other organs in 4T1 subcutaneous xenograft models. These features indicate that the designed liposomes represent a promising strategy for the reversal of MDR in cancer treatment.


Asunto(s)
Apolipoproteína A-I/química , Neoplasias de la Mama/tratamiento farmacológico , Doxorrubicina/análogos & derivados , Apolipoproteína A-I/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/química , Doxorrubicina/farmacología , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos/genética , Femenino , Humanos , Células MCF-7 , Polietilenglicoles/química , Polietilenglicoles/farmacología
9.
Molecules ; 26(5)2021 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-33652969

RESUMEN

Cytotoxic flavonoids of Murraya tetramera were investigated in this study. A novel flavonoid and twelve known flavonoids, including seven flavones (1-7), three flavanones (8-10), and three chalcones (11-13) were isolated from the leaves and twigs of Murraya tetramera. Chemical structures were elucidated by NMR combined with MS spectral analysis, and the new compound (6) was confirmed as 3',5'-dihydroxy-5,6,7,4'-tetramethoxyflavone. Furthermore, all the isolated flavonoids were evaluated for their cytotoxicities against murine melanoma cells (B16), and human breast cancer cells (MDA-MB-231) by CCK-8 assay. Among them, compounds 7, 13, and 5 exhibited potent cytotoxic activities against B16 cell lines (IC50 = 3.87, 7.00 and 8.66 µg/mL, respectively). Compounds 5, 13, and 12 displayed potent cytotoxicities against MDA-MB-231 cell lines (IC50 = 3.80, 5.95 and 7.89 µg/mL, respectively). According to the correlation of the structure and activity analysis, 5-hydroxyl and 8-methoxyl substituents of the flavone, 8-methoxyl substituent of the flavanone, and 3',5'-methoxyl substituents of the chalcone could be critical factors of the high cytotoxicity. The results indicated that the active flavonoids have potential to be developed as leading compounds for treating cancers.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Proliferación Celular/efectos de los fármacos , Flavonoides/farmacología , Murraya/química , Animales , Antineoplásicos Fitogénicos/química , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Chalconas/química , Chalconas/farmacología , Femenino , Flavonoides/química , Humanos , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/patología , Ratones , Estructura Molecular , Extractos Vegetales/química , Extractos Vegetales/farmacología , Hojas de la Planta/química
10.
Int J Nanomedicine ; 16: 1961-1976, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33727809

RESUMEN

Introduction: Metastatic breast cancer seriously harms women's health and is currently the tumour type with the highest mortality rate in women. Recently, the combinatorial therapeutic approaches that integrate anti-cancer drugs and genetic agents is an attractive and promising strategy for the treatment of metastatic breast cancer. Moreover, such a combination strategy requires better drug carriers that can effectively deliver the cargo to the breast cancer cells and achieve controlled release in the cells to achieve better therapeutic effects. Methods: The tumour-targeted and redox-responsive mesoporous silica nanoparticles (MSNs) functionalised with DNA aptamers (AS1411) as a co-delivery system was developed and investigated for the potential against metastatic breast cancer. Doxorubicin (Dox) was loaded onto the MSNs, while AS1411 and a small interfering RNA (siTIE2) were employed as gatekeepers via attachment to the MSNs with redox-sensitive disulfide bonds. Results: The controlled release of Dox and siTIE2 was associated with intracellular glutathione. AS1411 mediated the targeted delivery of Dox by increasing its cellular uptake in metastatic breast cancer, ultimately resulting in a lower IC50 in MDA-MB-231 cells (human breast cancer cell line with high metastatic potency), improved biodistribution in tumour-bearing mice, and enhanced in vivo anti-tumour effects. The in vitro cell migration/invasion assay and in vivo anti-metastatic study revealed synergism in the co-delivery system that suppresses cancer cell metastasis. Conclusion: The tumour-targeted and redox-responsive MSN prepared in this study are promising for the effective delivery and controlled release of Dox and siTIE2 for improved treatment of metastatic breast cancer.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Doxorrubicina/uso terapéutico , Nanopartículas/química , ARN Interferente Pequeño/administración & dosificación , Dióxido de Silicio/química , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/patología , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Preparaciones de Acción Retardada/farmacología , Preparaciones de Acción Retardada/uso terapéutico , Doxorrubicina/farmacología , Portadores de Fármacos/química , Endocitosis/efectos de los fármacos , Femenino , Células HEK293 , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , Nanopartículas/ultraestructura , Invasividad Neoplásica , Metástasis de la Neoplasia , Oxidación-Reducción , Porosidad , ARN Interferente Pequeño/farmacología , Distribución Tisular/efectos de los fármacos
11.
Chem Biol Interact ; 339: 109432, 2021 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-33684387

RESUMEN

Mitochondrial dependent oxidative stress (OS) and subsequent cell death are considered as the major cytotoxicity caused by Triethylene glycol dimethacrylate (TEGDMA), a commonly monomer of many resin-based dental composites. Under OS microenvironment, autophagy serves as a cell homeostatic mechanism and maintains redox balance through degradation or turnover of cellular components in order to promote cell survival. However, whether autophagy is involved in the mitochondrial oxidative damage and apoptosis induced by TEGDMA, and the cellular signaling pathways underlying this process remain unclear. In the present study, we demonstrated that TEGDMA induced mouse preodontoblast cell line (mDPC6T) dysfunctional mitochondrial oxidative response. In further exploring the underlying mechanisms, we found that TEGDMA impaired autophagic flux, as evidenced by increased LC3-II expression and hindered p62 degradation, thereby causing both mitochondrial oxidative damage and cell apoptosis. These results were further verified by treatment with chloroquine (autophagy inhibitor) and rapamycin (autophagy promotor). More importantly, we found that the JNK/MAPK pathway was the key upstream regulator of above injury process. Collectively, our finding firstly demonstrated that TEGDMA induced JNK-dependent autophagy, thereby promoting mitochondrial dysfunction-associated oxidative damage and apoptosis in preodontoblast.


Asunto(s)
Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Estrés Oxidativo/efectos de los fármacos , Polietilenglicoles/farmacología , Ácidos Polimetacrílicos/farmacología , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , Cloroquina/farmacología , Ratones , Proteínas Asociadas a Microtúbulos/metabolismo , Oxidación-Reducción/efectos de los fármacos , Proteínas de Unión al ARN/metabolismo , Transducción de Señal/efectos de los fármacos , Sirolimus/farmacología
12.
Anticancer Res ; 41(3): 1243-1250, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33788715

RESUMEN

BACKGROUND/AIM: Breast cancer (BC) may be affected by diabetes and anti-diabetic medication, as well as its therapeutic agents. Low-dose metronomic chemotherapy (LDMC) is an available treatment option in BC. We investigated the impact of insulin on low-dose metronomic vinorelbine and mafosfamide in BC cell lines. MATERIALS AND METHODS: Human BC cell lines T-47D, MCF-7, MDA-MB-231, BT-549 and non-tumorigenic breast cell line MCF-10A were exposed to 0.01 µg/ml and 10 µg/ml insulin in combination with low-dose metronomic vinorelbine or mafosfamide. The cell viability was determined after 24-72 hours using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. RESULTS: Insulin, especially at a concentration of 10 µg/ml, seemed to increase viability of vinorelbine-treated hormone receptor-positive BC cells, whereas low-dose mafosfamide treatment tended to be potentiated by insulin in triple-negative cells. CONCLUSION: Our findings suggest that insulin may influence the cytotoxic activity of LDMC depending on insulin concentration, type of cytotoxic drug used and BC cell line.


Asunto(s)
Antineoplásicos/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Ciclofosfamida/análogos & derivados , Insulina/farmacología , Vinorelbina/administración & dosificación , Administración Metronómica , Neoplasias de la Mama/patología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Ciclofosfamida/administración & dosificación , Femenino , Humanos
13.
Anticancer Res ; 41(3): 1271-1282, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33788718

RESUMEN

BACKGROUND/AIM: We aimed to investigate the synergistic effects of apigenin and curcumin on the cross-talk between apoptosis and autophagic cell death, as well as on paraptosis in HeLa cells. MATERIALS AND METHODS: Cell viability was measured using the MTT assay. Synergistic effects were measured using the Bliss independence model. qRT-PCR was used to study the expression of genes related to apoptosis, autophagic cell death, and cross-talk. GRP78/BiP immunostaining was used to identify endoplasmic reticulum (ER) stress. RESULTS: Treatment with a combination of apigenin and curcumin increased the expression levels of genes related to cell death in HeLa cells 1.29- to 27.6-fold. The combination of curcumin and apigenin showed a synergistic anti-tumor effect via cross-talk between processes leading to apoptosis and autophagic cell death, as well as ER stress-associated paraptosis. GRP78 expression was down-regulated, and massive cytoplasmic vacuolization was observed in HeLa cells. CONCLUSION: The combination of curcumin and apigenin is an effective potential therapeutic for cervical cancers.


Asunto(s)
Apigenina/farmacología , Apoptosis/efectos de los fármacos , Muerte Celular Autofágica/efectos de los fármacos , Curcumina/farmacología , Proteínas Adaptadoras Transductoras de Señales/genética , Caspasa 3/fisiología , Supervivencia Celular/efectos de los fármacos , Sinergismo Farmacológico , Femenino , Células HeLa , Proteínas de Choque Térmico/análisis , Humanos , Proteínas de la Membrana/genética , Proteínas Proto-Oncogénicas/genética , Neoplasias del Cuello Uterino/tratamiento farmacológico
14.
Anticancer Res ; 41(3): 1357-1364, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33788727

RESUMEN

BACKGROUND/AIM: Amentoflavone, an effective compound derived from medicinal plants, has been shown to boost therapeutic efficacy of chemotherapy in non-small cell lung cancer (NSCLC). However, anti-NSCLC effect of amentoflavone is ambiguous. The major purpose of the present study was to verify the inhibitory effects of amentoflavone in NSCLC cells. MATERIALS AND METHODS: The effects of amentoflavone on growth and invasion of NSCLC CL-1-5-F4 cells were evaluated by cell viability assay, flow cytometry, colony formation assay, nuclear factor-kappa B (NF-κB) reporter gene assay, immunofluorescence staining, transwell invasion, and western blot assay. RESULTS: Amentoflavone effectively induced cell growth inhibition, G1 cell-cycle arrest, apoptosis, and suppression of invasion. Furthermore, amentoflavone not only triggered expression of p27, cleaved caspase-3, -8 also reduced NF-κB signaling, protein levels of matrix metalloproteinase (MMP)-2, -9, Cyclin-D1, and vascular endothelial growth factor (VEGF). CONCLUSION: Cell-cycle arrest, apoptosis induction, NF-κB signaling inhibition are associated with amentoflavone-inhibited growth and invasion of NSCLC cells.


Asunto(s)
Apoptosis/efectos de los fármacos , Biflavonoides/farmacología , Carcinoma de Pulmón de Células no Pequeñas/patología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Neoplasias Pulmonares/patología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Inhibidores del Citocromo P-450 CYP2C9/farmacología , Puntos de Control de la Fase G1 del Ciclo Celular , Humanos , Neoplasias Pulmonares/metabolismo , Metaloproteinasas de la Matriz/metabolismo , FN-kappa B/metabolismo , Invasividad Neoplásica , Transducción de Señal/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/metabolismo
15.
Anticancer Res ; 41(3): 1387-1399, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33788730

RESUMEN

BACKGROUND/AIM: Despite clinical benefit from treatment with dabrafenib and trametinib in melanoma patients with BRAF mutations, half relapse within months and one-third are unresponsive to treatment. We evaluated the anticancer potential of metformin in combination with trametinib plus paclitaxel, against four melanoma cell lines. MATERIALS AND METHODS: Metformin with trametinib and paclitaxel was tested for effects on cell viability, signaling molecules in MAPK and mTOR pathways, factors involved in epithelial-mesenchymal transition (EMT), and cell motility. RESULTS: The combination of metformin with trametinib and paclitaxel showed differential growth inhibitory effects; synergistic effects were observed in a cell line in which metformin suppresses ERK activity, whereas the combination showed antagonistic effects in a cell line with metformin-induced ERK activation. Trametinib or paclitaxel increased the expression of EMT regulators and melanoma cell motility, which were suppressed by combining metformin with trametinib and paclitaxel. CONCLUSION: The combined treatment of metformin with trametinib and paclitaxel showed divergent effects on melanoma cell viability. Metformin might be useful as a potential adjuvant against cell proliferation and metastatic activity in melanoma patients.


Asunto(s)
Melanoma/patología , Metformina/farmacología , Paclitaxel/farmacología , Piridonas/farmacología , Pirimidinonas/farmacología , Neoplasias Cutáneas/patología , Antineoplásicos/farmacología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Sinergismo Farmacológico , Transición Epitelial-Mesenquimal/efectos de los fármacos , Humanos , Melanoma/genética , Melanoma/metabolismo , Mutación , Proteínas Proto-Oncogénicas B-raf/genética , Transducción de Señal/efectos de los fármacos , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/metabolismo
16.
Anticancer Res ; 41(3): 1429-1438, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33788734

RESUMEN

BACKGROUND/AIM: Clinical significance of antitumour drugs is limited by multidrug resistance (MDR). We examined the effect of bioreductive activation of the anthracyclines, doxorubicin (DOX) and pirarubicin (PIRA), by cytochrome P450 reductase (CPR) on triggering apoptosis of leukaemia HL60 cells and their MDR counterparts. MATERIALS AND METHODS: Cell cycle and FAS expression were investigated by flow cytometry. DNA fragmentation was examined by electrophoretic analysis and caspase-3/8 activities were determined colorimetrically. RESULTS: Non-activated and CPR-activated forms of DOX and PIRA (IC90) had similar efficacy in provoking G2/M arrest of sensitive HL60 as well as resistant HL60/VINC and HL60/DOX cells and in causing DNA degradation. Interestingly, HL60/VINC cells were more prone to apoptosis induced by all studied forms of these drugs. However, no change in Fas expression was observed. CONCLUSION: Bioreductive activation of DOX and PIRA does not affect their ability to induce apoptosis of sensitive and resistant HL60 leukaemia cells.


Asunto(s)
Apoptosis/efectos de los fármacos , Doxorrubicina/análogos & derivados , Doxorrubicina/farmacología , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Leucemia/patología , Antineoplásicos/farmacología , Caspasa 3/metabolismo , Caspasa 8/metabolismo , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Fragmentación del ADN/efectos de los fármacos , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Células HL-60 , Humanos , Leucemia/metabolismo , NADPH-Ferrihemoproteína Reductasa/metabolismo
17.
Molecules ; 26(4)2021 Feb 22.
Artículo en Inglés | MEDLINE | ID: mdl-33671801

RESUMEN

Several derivatives containing morpholine/piperidine, anilines, and dipeptides as pending moieties were prepared using s-triazine as a scaffold. These compounds were evaluated for their anticancer activity against two human breast cancer cell lines (MCF-7 and MDA-MB-231), a colon cancer cell line (HCT-116), and a non-tumorigenic cell line (HEK 293). Tamoxifen was used as a reference. Animal toxicity tests were carried out in zebrafish embryos. Most of these compounds showed a higher activity against breast cancer than colon cancer. Compound 3a-which contains morpholine, aniline, and glycylglycinate methyl ester-showed a high level of cytotoxicity against MCF-7 cells with IC50 values of less than 1 µM. This compound showed a much lower level of toxicity against the non-tumorigenic HEK-293 cell line, and in the in vivo studies using zebrafish embryos. Furthermore, it induced cell cycle arrest at the G2/M phase, and apoptosis in MCF-7 cells. On the basis of our results, 3a emerges as a potential candidate for further development as a therapeutic drug to treat hormone receptor-positive breast cancer.


Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Dipéptidos/farmacología , Triazinas/farmacología , Animales , Antineoplásicos/síntesis 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 , Dipéptidos/síntesis química , Dipéptidos/química , Evaluación Preclínica de Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Triazinas/síntesis química , Triazinas/química , Pez Cebra/embriología
18.
Molecules ; 26(4)2021 Feb 23.
Artículo en Inglés | MEDLINE | ID: mdl-33672109

RESUMEN

The conservation of mammary gland physiology by maintaining the maximum number of mammary epithelial cells (MECs) is of the utmost importance for the optimum amount of milk production. In a state of negative energy balance, palmitic acid (PA) reduces the number of bovine MECs. However, there is no effective strategy against PA-induced apoptosis of MECs. In the present study, 5-aminolevulinic acid (5-ALA) was established as a remedial agent against PA-induced apoptosis of MAC-T cells (an established line of bovine MECs). In PA-treated cells, the apoptosis-related genes BCL2 and BAX were down- and upregulated, respectively. The elevated expression of major genes of the unfolded protein response (UPR), such as CHOP, a proapoptotic marker (C/EBP homologous protein), reduced the viability of PA-treated MAC-T cells. In contrast, 5-ALA pretreatment increased and decreased BCL2 and BAX expression, respectively. Moreover, cleaved caspase-3 protein expression was significantly reduced in the 5-ALA-pretreated group in comparison with the PA group. The downregulation of major UPR-related genes, including CHOP, extended the viability of MAC-T cells pretreated with 5-ALA and also reduced the enhanced intensity of the PA-induced expression of phospho-protein kinase R-like ER kinase. Moreover, the enhanced expression of HO-1 (antioxidant gene heme oxygenase) by 5-ALA reduced PA-induced oxidative stress (OxS). HO-1 is not only protective against OxS but also effective against ER stress. Collectively, these findings offer new insights into the protective effects of 5-ALA against PA-induced apoptosis of bovine MECs.


Asunto(s)
Ácido Aminolevulínico/farmacología , Apoptosis/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Glándulas Mamarias Animales/efectos de los fármacos , Ácido Palmítico/antagonistas & inhibidores , Animales , Bovinos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Estrés del Retículo Endoplásmico/efectos de los fármacos , Estructura Molecular , Ácido Palmítico/farmacología , Relación Estructura-Actividad
19.
Molecules ; 26(5)2021 Feb 25.
Artículo en Inglés | MEDLINE | ID: mdl-33668689

RESUMEN

Rapamycin is an antifungal drug with antitumor activity and acts inhibiting the mTOR complex. Due to drug antitumor potential, the aim of this study was to evaluate its effect on a preclinical model of primary mammary gland tumors and their metastases from female dogs. Four cell lines from our cell bank, two from primary canine mammary tumors (UNESP-CM1, UNESP-CM60) and two metastases (UNESP-MM1, and UNESP-MM4) were cultured in vitro and investigated for rapamycin IC50. Then, cell lines were treated with rapamycin IC50 dose and mRNA and protein were extracted in treated and non-treated cells to perform AKT, mTOR, PTEN and 4EBP1 gene expression and global proteomics by mass spectrometry. MTT assay demonstrated rapamycin IC50 dose for all different tumor cells between 2 and 10 µM. RT-qPCR from cultured cells, control versus treated group and primary tumor cells versus metastatic tumor cells, did not shown statistical differences. In proteomics were found 273 proteins in all groups, and after data normalization 49 and 92 proteins were used for statistical analysis for comparisons between control versus rapamycin treatment groups, and metastasis versus primary tumor versus metastasis rapamycin versus primary tumor rapamycin, respectively. Considering the two statistical analysis, four proteins, phosphoglycerate mutase, malate dehydrogenase, l-lactate dehydrogenase and nucleolin were found in decreased abundance in the rapamycin group and they are related with cellular metabolic processes and enhanced tumor malignant behavior. Two proteins, dihydrolipoamide dehydrogenase and superoxide dismutase, also related with metabolic processes, were found in higher abundance in rapamycin group and are associated with apoptosis. The results suggested that rapamycin was able to inhibit cell growth of mammary gland tumor and metastatic tumors cells in vitro, however, concentrations needed to reach the IC50 were higher when compared to other studies.


Asunto(s)
Antibióticos Antineoplásicos/farmacología , Neoplasias Mamarias Animales/tratamiento farmacológico , Proteómica , Sirolimus/farmacología , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Perros , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Neoplasias Mamarias Animales/metabolismo , Neoplasias Mamarias Animales/patología , Espectrometría de Masas , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Células Tumorales Cultivadas
20.
Molecules ; 26(5)2021 Feb 25.
Artículo en Inglés | MEDLINE | ID: mdl-33668690

RESUMEN

The Mongolian rhubarb-Rheum undulatum L. (RU)-and Rumex crispus L. (RC)-a Taiwanese local rhubarb belonging to the family of Polygonaceae-are principal therapeutic materials in integrative medicine due to their rich quantities of bioactive compounds; however, their phytochemical and antioxidant properties, and anti-cancer activity is poorly investigated. Furthermore, the phytochemical characteristics of both species may be affected by their different geographical distribution and climatic variance. The current study aimed to compare RU with RC extracts in different polarity solvents (n-hexane, ethyl acetate, acetone, ethanol, and water) for their phytochemical contents including the total phenolic content (TPC), total anthraquinone content (TAC), total flavonoid content (TFC), antioxidant and free radical scavenging capacities, and anticancer ability on the HepG2 cell. Except for the n-hexane extract, all of the RU extracts had considerably higher TPCs than RC extracts, ranging from 8.39 to 11.16 mg gallic acid equivalent (GAE) per gram of dry weight, and the TPCs of each extract were also significantly correlated with their antioxidant capacities by ABTS, DPPH, and FRAP assays (p < 0.05). Moreover, there was no remarkable association between the antioxidant capacities and either TACs or TFCs in both the RU and RC extracts. Besides, high-performance liquid chromatography (HPLC) analysis revealed that both the RU and RC extracts contained chrysophanol, emodin, and physcion, and those bioactive compounds were relatively higher in the n-hexane solvent extracts. Additionally, we observed different levels of dose-dependent cytotoxic effects in all the extracts by cell viability assay. Notably, the ethanol extract of RU had a compelling cytotoxic effect with the lowest half-maximum inhibition concentration (IC50-171.94 ± 6.56 µg/mL at 48 h) among the RU extracts than the ethanol extract of RC. Interestingly, the ethanol extract of RU but not RC significantly induced apoptosis in the human liver cancer cell line, HepG2, with a distinct pattern in caspase-3 activation, resulting in increased PARP cleavage and DNA damage. In summary, Mongolian Rhubarb, RU, showed more phytochemical contents, as well as a higher antioxidant capacity and apoptotic effect to HepG2 than RC; thus, it can be exploited for the proper source of natural antioxidants and liver cancer treatment in further investigation.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Antioxidantes/farmacología , Fitoquímicos/farmacología , Extractos Vegetales/farmacología , Rheum/química , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Antioxidantes/química , Antioxidantes/aislamiento & purificación , Benzotiazoles/antagonistas & inhibidores , Compuestos de Bifenilo/antagonistas & inhibidores , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células Hep G2 , Humanos , Mongolia , Fitoquímicos/química , Fitoquímicos/aislamiento & purificación , Picratos/antagonistas & inhibidores , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Relación Estructura-Actividad , Ácidos Sulfónicos/antagonistas & inhibidores , Taiwán , Células Tumorales Cultivadas
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