Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 18.066
Filtrar
1.
Molecules ; 26(5)2021 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-33804495

RESUMEN

From the soft coral Xenia umbellata, seven isoprenoid derivatives were isolated, including a new xenicane diterpene, xeniolide O (5) and a new gorgostane derivative gorgst-3ß,5α,6ß,11α,20(S)-pentol-3-monoacetate (7), along with three known sesquiterpenes (1-3), a known diterpene (4), and a known steroid (6). The extensive analyses of the NMR, IR, and MS spectral data led to determination of their chemical structures. Compounds 1-7 displayed a cytotoxic effect against breast adenocarcinoma (MCF-7), hepatocellular carcinoma (HepG2), and cervix adenocarcinoma (HeLa), with IC50 values ranging between 1.5 ± 0.1-23.2 ± 1.5; 1.8 ± 0.1-30.6 ± 1.1 and 0.9 ± 0.05-12.8 ± 0.5 µg/mL, respectively. Compound 3 showed potent cytotoxic effects against MCF-7, HepG2, and HeLa with IC50 values = 2.4 ± 0.20, 3.1 ± 0.10 and 0.9 ± 0.05 µg/mL, respectively. Compounds 2, 5, and 7 displayed cytotoxic effect against Hela cells with IC50 values = 12.8 ± 0.50, 6.7 ± 1.00 and 11.5 ± 2.20 µg/mL, respectively. Two DNA binding dyes, acridine orange (AO) and ethidium bromide (EtBr) were used for the detection of viable, apoptotic, and necrotic cells. The early apoptotic cell death was observed in all types of treated cells. The late apoptotic cells were highly present in HepG2 cells. Compounds 5 and 7 induced a high percentage of necrosis towards HepG2 and HeLa cells. The late apoptosis was recorded as a high rate after treatment with 7 on all cancer cells.


Asunto(s)
Antozoos/química , Antineoplásicos/farmacología , Proliferación Celular , Neoplasias/tratamiento farmacológico , Terpenos/química , Terpenos/farmacología , Animales , Antineoplásicos/química , Apoptosis , Células HeLa , Células Hep G2 , Humanos , Células MCF-7 , Estructura Molecular , Neoplasias/patología
2.
Int J Mol Sci ; 22(5)2021 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-33800170

RESUMEN

IL-34 has been recently identified as a ligand for CSF1R that regulates various cellular processes including cell proliferation, survival, and differentiation. Although the binding of IL-34 to CSF1R modulates several cancer-driving signaling pathways, little is known about the role of IL-34/CSF1R signaling in breast cancer. Herein, we report that IL-34 induces epithelial cell transformation and breast tumorigenesis through activation of MEK/ERK and JNK/c-Jun pathways. IL-34 increased the phosphorylation of MEK1/2, ERK1/2, JNK1/2, and c-Jun through CSF1R in mouse skin epidermal JB6 C141 cells and human breast cancer MCF7 cells. IL-34 enhanced c-Fos and c-Jun promoter activity, resulting in increased AP-1 transactivation activity in JB6 Cl41 and MCF7 cells. Moreover, PIN1 enhanced IL-34-induced phosphorylation of MEK1/2, ERK1/2, JNK1/2, and c-Jun in JB6 Cl41 and MCF7 cells. Inhibition of PIN1 using juglone prevented the IL-34-induced transformation of JB6 C141 cells. Similarly, silencing of PIN1 reduced the IL-34-induced tumorigenicity of MCF7 cells. Consistent with these results, the synergistic model showed that treatment with juglone suppressed the IL-34-induced growth of tumors formed by 4T1 cells in BALB/c mice. Our study demonstrates the role of IL-34-induced MEK/ERK and JNK/c-Jun cascades in breast cancer and highlights the regulatory role of PIN1 in IL-34-induced breast tumorigenesis.


Asunto(s)
Neoplasias de la Mama/metabolismo , Transformación Celular Neoplásica/metabolismo , Células Epiteliales/metabolismo , Interleucinas/metabolismo , Sistema de Señalización de MAP Quinasas , Proteínas de Neoplasias/metabolismo , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Animales , Neoplasias de la Mama/patología , Transformación Celular Neoplásica/patología , Células Epiteliales/patología , Femenino , Humanos , Células MCF-7 , Ratones , Ratones Endogámicos BALB C
3.
Int J Mol Sci ; 22(5)2021 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-33800505

RESUMEN

Chemotherapy represents the most applied approach to cancer treatment. Owing to the frequent onset of chemoresistance and tumor relapses, there is an urgent need to discover novel and more effective anticancer drugs. In the search for therapeutic alternatives to treat the cancer disease, a series of hybrid pyrazolo[3,4-d]pyrimidin-4(5H)-ones tethered with hydrazide-hydrazones, 5a-h, was synthesized from condensation reaction of pyrazolopyrimidinone-hydrazide 4 with a series of arylaldehydes in ethanol, in acid catalysis. In vitro assessment of antiproliferative effects against MCF-7 breast cancer cells, unveiled that 5a, 5e, 5g, and 5h were the most effective compounds of the series and exerted their cytotoxic activity through apoptosis induction and G0/G1 phase cell-cycle arrest. To explore their mechanism at a molecular level, 5a, 5e, 5g, and 5h were evaluated for their binding interactions with two well-known anticancer targets, namely the epidermal growth factor receptor (EGFR) and the G-quadruplex DNA structures. Molecular docking simulations highlighted high binding affinity of 5a, 5e, 5g, and 5h towards EGFR. Circular dichroism (CD) experiments suggested 5a as a stabilizer agent of the G-quadruplex from the Kirsten ras (KRAS) oncogene promoter. In the light of these findings, we propose the pyrazolo-pyrimidinone scaffold bearing a hydrazide-hydrazone moiety as a lead skeleton for designing novel anticancer compounds.


Asunto(s)
Apoptosis/efectos de los fármacos , Neoplasias de la Mama , Proliferación Celular/efectos de los fármacos , G-Cuádruplex , Simulación del Acoplamiento Molecular , Proteínas Proto-Oncogénicas p21(ras) , Pirimidinonas , Antineoplásicos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Ensayos de Selección de Medicamentos Antitumorales , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/química , Receptores ErbB/metabolismo , Femenino , Humanos , Células MCF-7 , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Proteínas Proto-Oncogénicas p21(ras)/química , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Pirimidinonas/síntesis química , Pirimidinonas/química , Pirimidinonas/farmacología
4.
Int J Mol Sci ; 22(6)2021 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-33802075

RESUMEN

The high biological activity of the chromene compounds coupled with the intriguing optical features of azo chromophores prompted our desire to construct novel derivatives of chromene incorporating azo moieties 4a-l, which have been prepared via a three-component reaction of 1-naphthalenol-4-[(4-ethoxyphenyl) azo], 1, with the benzaldehyde derivatives and malononitrile. The structural identities of the azo-chromene 4a-l were confirmed on the basis of their spectral data and elemental analysis, and a UV-visible study was performed in a Dimethylformamide (DMF) solution for these molecules. Additionally, the antimicrobial activity was investigated against four human pathogens (Gram-positive and Gram-negative bacteria) and four fungi, employing an agar well diffusion method, with their minimum inhibitory concentrations being reported. Molecules 4a, 4g, and 4h were discovered to be more efficacious against Syncephalastrum racemosum (RCMB 05922) in comparison to the reference drugs, while compounds 4b and 4h demonstrated the highest inhibitory activity against Escherichia coli (E. coli) in evaluation against the reference drugs. Moreover, their cytotoxicity was assessed against three different human cell lines, including human colon carcinoma (HCT-116), human hepatocellular carcinoma (HepG-2), and human breast adenocarcinoma (MCF-7) with a selection of molecules illustrating potency against the HCT-116 and MCF-7 cell lines. Furthermore, the molecular modeling results depicted the binding interactions of the synthesized compounds 3b and 3h in the active site of the E. coli DNA gyrase B enzyme with a clear SAR (structure-activity relationship) analysis. Lastly, the density functional theory's (DFTs) theoretical calculations were performed to quantify the energy levels of the Frontier Molecular Orbitals (FMOs) and their energy gaps, dipole moments, and molecular electrostatic potentials. These data were utilized in the chemical descriptor estimations to confirm the biological activity.


Asunto(s)
Antiinfecciosos , Antineoplásicos , Compuestos Azo , Benzopiranos , Proliferación Celular/efectos de los fármacos , Simulación por Computador , Escherichia coli/crecimiento & desarrollo , Mucorales/crecimiento & desarrollo , Neoplasias/tratamiento farmacológico , Antiinfecciosos/síntesis química , Antiinfecciosos/química , Antiinfecciosos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Compuestos Azo/síntesis química , Compuestos Azo/química , Compuestos Azo/farmacología , Benzopiranos/síntesis química , Benzopiranos/química , Benzopiranos/farmacología , Células HCT116 , Células Hep G2 , Humanos , Células MCF-7 , Neoplasias/metabolismo , Neoplasias/patología
5.
Int J Mol Sci ; 22(5)2021 Mar 03.
Artículo en Inglés | MEDLINE | ID: mdl-33802299

RESUMEN

Selenium is an essential micronutrient with a wide range of biological effects in mammals. The inorganic form of selenium, selenite, is supplemented to relieve individuals with selenium deficiency and to alleviate associated symptoms. Additionally, physiological and supranutritional selenite have shown selectively higher affinity and toxicity towards cancer cells, highlighting their potential to serve as chemotherapeutic agents or adjuvants. At varying doses, selenite extensively regulates cellular signaling and modulates many cellular processes. In this study, we report the identification of Delta-Notch signaling as a previously uncharacterized selenite inhibited target. Our transcriptomic results in selenite treated primary mouse hepatocytes revealed that the transcription of Notch1, Notch2, Hes1, Maml1, Furin and c-Myc were all decreased following selenite treatment. We further showed that selenite can inhibit Notch1 expression in cultured MCF7 breast adenocarcinoma cells and HEPG2 liver carcinoma cells. In mice acutely treated with 2.5 mg/kg selenite via intraperitoneal injection, we found that Notch1 expression was drastically lowered in liver and kidney tissues by 90% and 70%, respectively. Combined, these results support selenite as a novel inhibitor of Notch signaling, and a plausible mechanism of inhibition has been proposed. This discovery highlights the potential value of selenite applied in a pathological context where Notch is a key drug target in diseases such as cancer, fibrosis, and neurodegenerative disorders.


Asunto(s)
Receptores Notch/metabolismo , Ácido Selenioso/farmacología , Transducción de Señal/efectos de los fármacos , Animales , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Femenino , Células Hep G2 , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Células MCF-7 , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Selenio/metabolismo , Transcriptoma/efectos de los fármacos
6.
Int J Mol Sci ; 22(5)2021 Mar 03.
Artículo en Inglés | MEDLINE | ID: mdl-33802613

RESUMEN

This study demonstrates the rational fabrication of a magnetic composite nanofiber mesh that can achieve mutual synergy of hyperthermia, chemotherapy, and thermo-molecularly targeted therapy for highly potent therapeutic effects. The nanofiber is composed of biodegradable poly(ε-caprolactone) with doxorubicin, magnetic nanoparticles, and 17-allylamino-17-demethoxygeldanamycin. The nanofiber exhibits distinct hyperthermia, owing to the presence of magnetic nanoparticles upon exposure of the mesh to an alternating magnetic field, which causes heat-induced cell killing as well as enhanced chemotherapeutic efficiency of doxorubicin. The effectiveness of hyperthermia is further enhanced through the inhibition of heat shock protein activity after hyperthermia by releasing the inhibitor 17-allylamino-17-demethoxygeldanamycin. These findings represent a smart nanofiber system for potent cancer therapy and may provide a new approach for the development of localized medication delivery.


Asunto(s)
Benzoquinonas/farmacología , Preparaciones de Acción Retardada/farmacología , Doxorrubicina/farmacología , Lactamas Macrocíclicas/farmacología , Nanofibras/química , Neoplasias/tratamiento farmacológico , Benzoquinonas/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Preparaciones de Acción Retardada/química , Doxorrubicina/química , Liberación de Fármacos , Sinergismo Farmacológico , Compuestos Férricos/química , Humanos , Lactamas Macrocíclicas/química , Células MCF-7 , Magnetismo/métodos , Nanopartículas de Magnetita/química
7.
Int J Mol Sci ; 22(7)2021 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-33810274

RESUMEN

The carbazole compounds PK9320 (1-(9-ethyl-7-(furan-2-yl)-9H-carbazol-3-yl)-N-methylmethanamine) and PK9323 (1-(9-ethyl-7-(thiazol-4-yl)-9H-carbazol-3-yl)-N-methylmethanamine), second-generation analogues of PK083 (1-(9-ethyl-9H-carbazol-3-yl)-N-methylmethanamine), restore p53 signaling in Y220C p53-mutated cancer cells by binding to a mutation-induced surface crevice and acting as molecular chaperones. In the present paper, these three molecules have been tested for mutant p53-independent genotoxic and epigenomic effects on wild-type p53 MCF-7 breast adenocarcinoma cells, employing a combination of Western blot for phospho-γH2AX histone, Comet assay and methylation-sensitive arbitrarily primed PCR to analyze their intrinsic DNA damage-inducing and DNA methylation-changing abilities. We demonstrate that small modifications in the substitution patterns of carbazoles can have profound effects on their intrinsic genotoxic and epigenetic properties, with PK9320 and PK9323 being eligible candidates as "anticancer compounds" and "anticancer epi-compounds" and PK083 a "damage-corrective" compound on human breast adenocarcinoma cells. Such different properties may be exploited for their use as anticancer agents and chemical probes.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Mama/metabolismo , Carbazoles/farmacología , Mutágenos/farmacología , Antineoplásicos/química , Neoplasias de la Mama/genética , Carbazoles/química , Daño del ADN , Metilación de ADN , Epigénesis Genética/efectos de los fármacos , Femenino , Histonas/metabolismo , Humanos , Células MCF-7 , Mutágenos/química , Transducción de Señal , Proteína p53 Supresora de Tumor/metabolismo
8.
Int J Mol Sci ; 22(5)2021 Mar 09.
Artículo en Inglés | MEDLINE | ID: mdl-33803480

RESUMEN

1,25-Dihydroxycholecalciferol, the hormonally active vitamin D3 metabolite, is known to exhibit therapeutic effects against breast cancer, mainly by lowering the expression of estrogen receptors and aromatase activity. Previously, the safety of the vitamin D active metabolite (24R)-1,24-dihydroxycholecalciferol (PRI-2191) and 1,25(OH)2D3 analog PRI-2205 was tested, and the in vitro activity of these analogs against different cancer cell lines was studied. We determined the effect of the two vitamin D compounds on anastrozole (An) activity against breast cancer based on antiproliferative activity, ELISA, flow cytometry, enzyme inhibition potency, PCR, and xenograft study. Both the vitamin D active metabolite and synthetic analog regulated the growth of not only estrogen receptor-positive cells (T47D and MCF-7, in vitro and in vivo), but also hormone-independent cancer cells such as SKBR-3 (HER-2-positive) and MDA-MB-231 (triple-negative), despite their relatively low VDR expression. Combined with An, PRI-2191 and PRI-2205 significantly inhibited the tumor growth of MCF-7 cells. Potentiation of the antitumor activity in combined treatment of MCF-7 tumor-bearing mice is related to the reduced activity of aromatase by both An (enzyme inhibition) and vitamin D compounds (switched off/decreased aromatase gene expression, decreased expression of other genes related to estrogen signaling) and by regulation of the expression of the estrogen receptor ERα and VDR.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Anastrozol/agonistas , Anastrozol/farmacología , Animales , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Calcitriol/análogos & derivados , Calcitriol/farmacología , Dihidroxicolecalciferoles/farmacología , Femenino , Humanos , Células MCF-7 , Ratones , Ratones SCID , Ensayos Antitumor por Modelo de Xenoinjerto
9.
Int J Mol Sci ; 22(5)2021 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-33806648

RESUMEN

Heterogeneous nuclear ribonucleoprotein K (hnRNPK) transcripts are abundant in estrogen receptor (ER)- or progesterone receptor (PR)-positive breast cancer. However, the biological functions of hnRNPK in the ER-mediated signaling pathway have remained largely unknown. Therefore, this study analyzes the functions of hnRNPK expression in the ER-mediated signaling pathway in breast cancer. We initially evaluated hnRNPK expression upon treatment with estradiol (E2) and ICI 182,780 in the ERα-positive breast carcinoma cell line MCF-7. The results revealed that E2 increased hnRNPK; however, hnRNPK expression was decreased with ICI 182,780 treatment, indicating estrogen dependency. We further evaluated the effects of hnRNPK knockdown in the ER-mediated signaling pathway in MCF-7 cells using small interfering RNAs. The results revealed that hnRNPK knockdown decreased ERα expression and ERα target gene pS2 by E2 treatment. As hnRNPK interacts with several other proteins, we explored the interaction between hnRNPK and ERα, which was demonstrated using immunoprecipitation and proximity ligation assay. Subsequently, we immunolocalized hnRNPK in patients with breast cancer, which revealed that hnRNPK immunoreactivity was significantly higher in ERα-positive carcinoma cells and significantly lower in Ki67-positive or proliferative carcinoma cells. These results indicated that hnRNPK directly interacted with ERα and was involved in the ER-mediated signaling pathway in breast carcinoma. Furthermore, hnRNPK expression could be an additional target of endocrine therapy in patients with ERα-positive breast cancer.


Asunto(s)
Neoplasias de la Mama/metabolismo , Estrógenos/metabolismo , Ribonucleoproteína Heterogénea-Nuclear Grupo K/metabolismo , Transducción de Señal/fisiología , Carcinoma/metabolismo , Línea Celular Tumoral , Proliferación Celular/fisiología , Femenino , Regulación Neoplásica de la Expresión Génica/fisiología , Humanos , Células MCF-7 , ARN Interferente Pequeño/metabolismo , Receptores Estrogénicos/metabolismo
10.
Int J Mol Sci ; 22(6)2021 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-33805656

RESUMEN

17ß-estradiol (E2) exerts its physiological effects through the estrogen receptor α (i.e., ERα). The E2:ERα signaling allows the regulation of cell proliferation. Indeed, E2 sustains the progression of ERα positive (ERα+) breast cancers (BCs). The presence of ERα at the BC diagnosis drives their therapeutic treatment with the endocrine therapy (ET), which restrains BC progression. Nonetheless, many patients develop metastatic BCs (MBC) for which a treatment is not available. Consequently, the actual challenge is to complement the drugs available to fight ERα+ primary and MBC. Here we exploited a novel anti-estrogen discovery platform to identify new Food and Drug Administration (FDA)-approved drugs inhibiting E2:ERα signaling to cell proliferation in cellular models of primary and MBC cells. We report that the anti-fungal drugs clotrimazole (Clo) and fenticonazole (Fenti) induce ERα degradation and prevent ERα transcriptional signaling and proliferation in cells modeling primary and metastatic BC. The anti-proliferative effects of Clo and Fenti occur also in 3D cancer models (i.e., tumor spheroids) and in a synergic manner with the CDK4/CDK6 inhibitors palbociclib and abemaciclib. Therefore, Clo and Fenti behave as "anti-estrogens"-like drugs. Remarkably, the present "anti-estrogen" discovery platform represents a valuable method to rapidly identify bioactive compounds with anti-estrogenic activity.


Asunto(s)
Aminopiridinas/farmacología , Antineoplásicos/farmacología , Bencimidazoles/farmacología , Clotrimazol/farmacología , Receptor alfa de Estrógeno/antagonistas & inhibidores , Imidazoles/farmacología , Piperazinas/farmacología , Piridinas/farmacología , Antifúngicos/farmacología , Ciclo Celular/efectos de los fármacos , Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/genética , Quinasa 4 Dependiente de la Ciclina/metabolismo , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/genética , Quinasa 6 Dependiente de la Ciclina/metabolismo , Aprobación de Drogas , Descubrimiento de Drogas , Reposicionamiento de Medicamentos , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Sinergismo Farmacológico , Estradiol/metabolismo , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Células MCF-7 , Proteolisis , Transducción de Señal , Esferoides Celulares/efectos de los fármacos , Esferoides Celulares/metabolismo , Esferoides Celulares/patología
11.
Nat Commun ; 12(1): 1998, 2021 03 31.
Artículo en Inglés | MEDLINE | ID: mdl-33790302

RESUMEN

The heterogeneity of breast cancer plays a major role in drug response and resistance and has been extensively characterized at the genomic level. Here, a single-cell breast cancer mass cytometry (BCMC) panel is optimized to identify cell phenotypes and their oncogenic signalling states in a biobank of patient-derived tumour xenograft (PDTX) models representing the diversity of human breast cancer. The BCMC panel identifies 13 cellular phenotypes (11 human and 2 murine), associated with both breast cancer subtypes and specific genomic features. Pre-treatment cellular phenotypic composition is a determinant of response to anticancer therapies. Single-cell profiling also reveals drug-induced cellular phenotypic dynamics, unravelling previously unnoticed intra-tumour response diversity. The comprehensive view of the landscapes of cellular phenotypic heterogeneity in PDTXs uncovered by the BCMC panel, which is mirrored in primary human tumours, has profound implications for understanding and predicting therapy response and resistance.


Asunto(s)
Benzamidas/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Xenoinjertos/efectos de los fármacos , Morfolinas/farmacología , Piperazinas/farmacología , Piridinas/farmacología , Pirimidinas/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Femenino , Xenoinjertos/metabolismo , Humanos , Células MCF-7 , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID , Inhibidores de Proteínas Quinasas/farmacología , Resultado del Tratamiento
12.
Int J Nanomedicine ; 16: 2501-2513, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33824588

RESUMEN

Introduction: Aim to obtain a NO donor that can control released NO in vivo with the high efficacy of tumor suppression and targeting, a nanoplatform consisting of FA-Fe3O4@mSiO2-Au/DOX was constructed. Methods: In vitro, the nanoplatform catalyzed NO's release with the maximum value of 4.91 µM within 60 min at 43°C pH=5.0, which was increased by 1.14 times when the temperature was 37°C. In vivo, 11.7 µg Au in the tumor tissue was found to catalyze S-nitrosoglutathione continuously, and 54 µM NO was checked out in the urine. Results and Discussion: The high concentration of NO was found to increase the apoptotic rate and to reduce tumor proliferation. In the chemo-photothermal combination therapy, the tumor inhibition rate was increased up to 94.3%, and Au's contribution from catalyzing NO release NO was 8.17%.


Asunto(s)
Oro/química , Neoplasias/patología , Neoplasias/terapia , Óxido Nítrico/metabolismo , Catálisis , Muerte Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Liberación de Fármacos , Endocitosis/efectos de los fármacos , Ácido Fólico/química , Humanos , Células MCF-7 , Fenómenos Magnéticos , Nanopartículas/química , Nanopartículas/ultraestructura , Tamaño de la Partícula , Porosidad , Silicio/química , Difracción de Rayos X
13.
Int J Nanomedicine ; 16: 2533-2553, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33824590

RESUMEN

Purpose: The present study was intended to fabricate chitosan (Ch)-tamarind gum polysaccharide (TGP) polyelectrolyte complex stabilized cubic nanoparticles of simvastatin and evaluate their potential against human breast cancer cell lines. Materials and Methods: The antisolvent precipitation method was used for formulation of nanoparticles. Factorial design (32) was utilized as a tool to analyze the effect of Ch and TGP concentration on particle size and entrapment efficiency of nanoparticles. Results: Formulated nanoparticles showed high entrapment efficiency (67.19±0.42-83.36±0.23%) and small size (53.3-383.1 nm). The present investigation involved utilization of two biological membranes (egg and tomato) as biological barriers for drug release. The study revealed that drug release from tomato membranes was retarded (as compared to egg membranes) but the release pattern matched that of egg membranes. All formulations followed the Baker-Lansdale model of drug release irrespective of the two different biological barriers. Stability studies were carried out for 45 days and exhibited less variation in particle size as well as a reduction in entrapment efficiency. Simvastatin loaded PEC stabilized nanoparticles exhibited better control on growth of human breast cancer cell lines than simple simvastatin. An unusual anticancer effect of simvastatin nanoparticles is also supported by several other research studies. Conclusion: The present study involves first-time synthesis of Ch-TGP polyelectrolyte complex stabilized nanoparticles of simvastatin against MCF-7 cells. It recommends that, in future, theoretical modeling and IVIVC should be carried out for perfect designing of delivery systems.


Asunto(s)
Quitosano/química , Nanopartículas/química , Gomas de Plantas/química , Polielectrolitos/química , Polisacáridos/química , Simvastatina/farmacología , Tamarindus/química , Antineoplásicos/farmacología , Muerte Celular/efectos de los fármacos , Portadores de Fármacos , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , Humanos , Células MCF-7 , Nanopartículas/ultraestructura , Tamaño de la Partícula , Espectrofotometría Infrarroja , Electricidad Estática
14.
Adv Exp Med Biol ; 1310: 385-399, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33834443

RESUMEN

Using the Raman spectroscopic analysis system that gives the chemical information of the biomaterials, classification is performed through the acquisition of fingerprint signals for each cell line, and the basis of the diagnosis is provided. The origin of diagnosis can be clarified by precise analysis through comparison of local signals and morphology in cells, including measurement at tissue level. In this result, normal breast cell line (MCF-10A) and breast cancer cell lines (MDA-MB-231, MDA-MB-453) were characterized using Raman spectroscopy, atomic force microscopy (AFM), and optical microscopy. These three modalities were combined in order to not only separate cancerous and noncancerous cell lines but to analyze their morphological and optical properties. From the results, the inherent optical properties of cancer cells separated from normal cells in terms of local variation were observed. Bright-field (BF) transmission imaging is also compared to the morphological height difference obtained from AFM and is correlated with surface Raman spectra.


Asunto(s)
Neoplasias , Espectrometría Raman , Mama , Línea Celular Tumoral , Humanos , Células MCF-7 , Microscopía de Fuerza Atómica
15.
Int J Nanomedicine ; 16: 2735-2749, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33859475

RESUMEN

Purpose: Nanocarriers, with a high drug loading content and good safety, to achieve desirable therapeutic effect are always the goals for industry and research. Methods and Results: In the present study, we developed a docetaxel loaded poly-2-oxazoline polymer micellar system which employed poly-2-butyl-2 oxazoline and poly-2-methyl-2 oxazoline as the hydrophobic chain and hydrophilic chain, respectively. This micellar system achieves a high load up to 25% against the docetaxel, and further demonstrates an IC50 as low as 40% of the commercialized docetaxel injection in vitro and a double maximum tolerated dose in MCF-7 cells in vivo. Conclusion: The high drug loading content, superior safety, and considerable anti-cancer activity make this newly developed docetaxel loaded poly(2-oxazoline) micelle go further in future clinical research.


Asunto(s)
Antineoplásicos/uso terapéutico , Docetaxel/uso terapéutico , Micelas , Neoplasias/tratamiento farmacológico , Oxazoles/química , Células A549 , Animales , Antineoplásicos/química , Apoptosis , Línea Celular Tumoral , Supervivencia Celular , Docetaxel/farmacología , Portadores de Fármacos/química , Liberación de Fármacos , Endocitosis/efectos de los fármacos , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Células MCF-7 , Masculino , Dosis Máxima Tolerada , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias/patología , Tamaño de la Partícula , Tensoactivos/química , Distribución Tisular
16.
Nat Commun ; 12(1): 2425, 2021 04 23.
Artículo en Inglés | MEDLINE | ID: mdl-33893275

RESUMEN

Anti-programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) antibodies are currently used in the clinic to interupt the PD-1/PD-L1 immune checkpoint, which reverses T cell dysfunction/exhaustion and shows success in treating cancer. Here, we report a histone demethylase inhibitor, 5-carboxy-8-hydroxyquinoline (IOX1), which inhibits tumour histone demethylase Jumonji domain-containing 1A (JMJD1A) and thus downregulates its downstream ß-catenin and subsequent PD-L1, providing an antibody-independent paradigm interrupting the PD-1/PD-L1 checkpoint. Synergistically, IOX1 inhibits cancer cells' P-glycoproteins (P-gp) through the JMJD1A/ß-catenin/P-gp pathway and greatly enhances doxorubicin (DOX)-induced immune-stimulatory immunogenic cell death. As a result, the IOX1 and DOX combination greatly promotes T cell infiltration and activity and significantly reduces tumour immunosuppressive factors. Their liposomal combination reduces the growth of various murine tumours, including subcutaneous, orthotopic, and lung metastasis tumours, and offers a long-term immunological memory function against tumour rechallenging. This work provides a small molecule-based potent cancer chemo-immunotherapy.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Doxorrubicina/farmacología , Hidroxiquinolinas/farmacología , Inmunoterapia/métodos , Neoplasias/terapia , Linfocitos T/efectos de los fármacos , Animales , Anticuerpos/inmunología , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/inmunología , Antígeno B7-H1/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/inmunología , Doxorrubicina/administración & dosificación , Células HCT116 , Humanos , Hidroxiquinolinas/administración & dosificación , Hidroxiquinolinas/química , Células MCF-7 , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Células 3T3 NIH , Neoplasias/inmunología , Neoplasias/metabolismo , Neoplasias Experimentales/inmunología , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/terapia , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Carga Tumoral/efectos de los fármacos , Carga Tumoral/inmunología
17.
Nat Commun ; 12(1): 2428, 2021 04 23.
Artículo en Inglés | MEDLINE | ID: mdl-33893291

RESUMEN

Heterochromatin is a critical chromatin compartment, whose integrity governs genome stability and cell fate transitions. How heterochromatin features, including higher-order chromatin folding and histone modifications associated with transcriptional silencing, are maintained following a genotoxic stress challenge is unknown. Here, we establish a system for targeting UV damage to pericentric heterochromatin in mammalian cells and for tracking the heterochromatin response to UV in real time. We uncover profound heterochromatin compaction changes during repair, orchestrated by the UV damage sensor DDB2, which stimulates linker histone displacement from chromatin. Despite massive heterochromatin unfolding, heterochromatin-specific histone modifications and transcriptional silencing are maintained. We unveil a central role for the methyltransferase SETDB1 in the maintenance of heterochromatic histone marks after UV. SETDB1 coordinates histone methylation with new histone deposition in damaged heterochromatin, thus protecting cells from genome instability. Our data shed light on fundamental molecular mechanisms safeguarding higher-order chromatin integrity following DNA damage.


Asunto(s)
Daño del ADN , Reparación del ADN , ADN/genética , Heterocromatina/genética , Animales , Línea Celular Tumoral , Ensamble y Desensamble de Cromatina/genética , ADN/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Heterocromatina/efectos de la radiación , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Histonas/metabolismo , Humanos , Células MCF-7 , Metilación , Ratones , Células 3T3 NIH , Rayos Ultravioleta
18.
Mol Med Rep ; 23(6)2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-33899120

RESUMEN

Fibronectin type III domain­containing protein 1 (FNDC1) is a protein that contains a major component of the structural domain of fibronectin. Although many studies have indicated that FNDC1 serves vital roles in the development of various diseases, the role of FNDC1 in the progression of breast cancer (BC) remains elusive. The aim of the present study was to investigate the biological functions of FNDC1 in BC cells and the associated mechanisms. The expression levels of FNDC1 in BC tissues and normal breast tissues were analyzed using The Cancer Genome Atlas database (TCGA). Kaplan­Meier curves were mined from TCGA to examine the clinical prognostic significance of FNDC1 mRNA in patients with BC. The expression of FNDC1 was knocked down by transfection with shRNA in BC cells. Cell viability, colony formation ability, migration and invasion were assayed following the silencing of FNDC1 in BC cells. The expression of proteins was measured using a western blotting assay. The bioinformatic data indicated that the FNDC1 mRNA expression levels were significantly upregulated in BC tissues compared with normal breast tissues, and the high mRNA expression levels of FNDC1 were associated with a lower overall survival in patients with BC. The downregulation of FNDC1 inhibited the proliferation, colony formation, migration and invasion of BC cells. Investigation of the mechanisms revealed that the silencing of FNDC1 decreased the protein expression levels of MMPs and epithelial­to­mesenchymal markers. Furthermore, the silencing of FNDC1 led to the inactivation of the PI3K/Akt signaling pathway. FNDC1 was highly upregulated and acted as an oncogene in BC. Therefore, targeting FNDC1 may be a potential strategy for the treatment of BC.


Asunto(s)
Neoplasias de la Mama/genética , Carcinogénesis/genética , Proteínas de Neoplasias/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de Señal , Neoplasias de la Mama/metabolismo , Línea Celular , Movimiento Celular , Supervivencia Celular , Femenino , Humanos , Células MCF-7 , Metaloproteinasas de la Matriz/metabolismo , Proteínas de Neoplasias/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Regulación hacia Arriba
19.
Molecules ; 26(6)2021 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-33799355

RESUMEN

Biocompatible tryptophan-derived copper (1) and zinc (2) complexes with norharmane (ß-carboline) were designed, synthesized, characterized, and evaluated for the potential anticancer activity in vitro and in vivo. The in vitro cytotoxicity of both complexes 1 and 2 were assessed against two cancerous cells: (human breast cancer) MCF7 and (liver hepatocellular cancer) HepG2 cells with a non-tumorigenic: (human embryonic kidney) HEK293 cells. The results exhibited a potentially decent selectivity of 1 against MCF7 cells with an IC50 value of 7.8 ± 0.4 µM compared to 2 (less active, IC50 ~ 20 µM). Furthermore, we analyzed the level of glutathione, lipid peroxidation, and visualized ROS generation to get an insight into the mechanistic pathway and witnessed oxidative stress. These in vitro results were ascertained by in vivo experiments, which also supported the free radical-mediated oxidative stress. The comet assay confirmed the oxidative stress that leads to DNA damage. The histopathology of the liver also ascertained the low toxicity of 1.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Carbolinas/farmacología , Cobre/farmacología , Triptófano/farmacología , Animales , Neoplasias de la Mama/metabolismo , Línea Celular , Línea Celular Tumoral , Ensayo Cometa/métodos , Daño del ADN/efectos de los fármacos , Femenino , Glutatión/metabolismo , Células HEK293 , Células Hep G2 , Humanos , Peroxidación de Lípido/efectos de los fármacos , Células MCF-7 , Estrés Oxidativo/efectos de los fármacos , Ratas , Especies Reactivas de Oxígeno/metabolismo , Zinc/farmacología
20.
Molecules ; 26(6)2021 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-33803877

RESUMEN

A novel series of N-1 arylidene amino imidazole-2-thiones were synthesized, identified using IR, 1H-NMR, and 13C-NMR spectral data. Cytotoxic effect of the prepared compounds was carried out utilizing three cancer cell lines; MCF-7 breast cancer, HepG2 liver cancer, and HCT-116 colon cancer cell lines. Imidazole derivative 5 was the most potent of all against three cell lines. DNA flow cytometric analysis showed that, imidazoles 4d and 5 exhibit pre-G1 apoptosis and cell cycle arrest at G2/M phase. The results of the VEGFR-2 and B-Raf kinase inhibition assay revealed that compounds 4d and 5 displayed good inhibitory activity compared with reference drug erlotinib.


Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Imidazoles/química , Imidazoles/farmacología , Antineoplásicos/síntesis química , Apoptosis/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Clorhidrato de Erlotinib/farmacología , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Células HCT116 , Células Hep G2 , Humanos , Imidazoles/síntesis química , Técnicas In Vitro , Células MCF-7 , Simulación del Acoplamiento Molecular , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Relación Estructura-Actividad , Tionas/síntesis química , Tionas/química , Tionas/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/química
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA
...