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1.
Int J Nanomedicine ; 16: 2373-2388, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33790555

RESUMEN

Aim: The metastasis of breast cancer is an important cause of tumor recurrence. This study highlights that tyrosine kinase inhibitors dasatinib (DAS) and rosiglitazone (ROZ) inhibit tumor growth and reduce the occurrence of tumor cell metastasis. Due to the poor water solubility, short half-time in the body of DAS and ROZ, which increases the difficulty of tumor treatment, as well as the demand for nano-drug delivery systems for organ-specific therapies. Methods: Hyaluronic acid (HA) and DAS are bonded by a pH-sensitive ester bond to form an HA-DAS polymer. Then, ROZ was added as the core, D-A-tocopherol polydiethylene glycol isosuccinate (TPGS) and HA-DAS were used as carriers to form HA-DAS and TPGS mixed micelle system loaded with ROZ (THDR-NPs). The size and structure of THDR-NPs were characterized, the drug release, stability and biosafety of THDR-NPs were studied. In vitro, the cytotoxicity, targeting effect and tumor metastasis inhibition of THDR-NPs were evaluated in human breast cancer cell lines. In addition, the selective potency of designed THDR-NPs in depleting was further verified in vivo in the tumor-bearing nude mice model. Results: The designed THDR-NPs have a particle size of less than 100 nm, good stability, biological safety and sustained release, and showed strong therapeutic effects on breast cancer models in vitro and in vivo. Moreover, it has been proved that THDR-NPs have the ability to inhibit tumor metastasis. Conclusion: DAS and ROZ were designed into micelles, the efficacy of THDR-NPs was higher than that of free drugs. These results indicate that nanoparticles have a good application prospect in the treatment of tumor metastasis.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , Animales , Peso Corporal/efectos de los fármacos , Neoplasias de la Mama/patología , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Dasatinib/administración & dosificación , Dasatinib/farmacocinética , Dasatinib/farmacología , Dasatinib/uso terapéutico , Portadores de Fármacos/química , Liberación de Fármacos , Endocitosis/efectos de los fármacos , Femenino , Hemólisis/efectos de los fármacos , Humanos , Ácido Hialurónico/química , Ratones Endogámicos BALB C , Ratones Desnudos , Micelas , Nanopartículas/química , Nanopartículas/ultraestructura , Tamaño de la Partícula , Espectroscopía de Protones por Resonancia Magnética , Ratas Sprague-Dawley , Rosiglitazona/farmacocinética , Rosiglitazona/farmacología , Rosiglitazona/uso terapéutico , Electricidad Estática , Distribución Tisular/efectos de los fármacos , Carga Tumoral/efectos de los fármacos
2.
Anticancer Res ; 41(4): 1779-1784, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33813382

RESUMEN

BACKGROUND/AIM: Osteosarcoma is a rare type of bone cancer that affects mostly children and adolescents. First-line chemotherapy for osteosarcoma has not been improved for many decades. Eribulin has been used to treat breast cancer and liposarcoma in the clinic. MATERIALS AND METHODS: A patient-derived orthotopic xenograft (PDOX) mouse model of osteosarcoma was established by tumor insertion within the tibia. This model more closely mimics osteosarcoma in clinical settings and was used to test the efficacy of eribulin. Tibia-insertion osteosarcoma PDOX mouse models were randomized into two groups: a control group (n=4) and an eribulin-treatment group (n=5). Mice were treated for fourteen days, four weeks after initial implantation. Tumor size and body weight were measured, and tumor histology was examined. RESULTS: Significant tumor growth inhibition (p=0.044) was observed in mice treated with eribulin compared to the control group. Histology demonstrated necrosis in the eribulin-treated tumors. There was no body-weight loss in the treated mice. CONCLUSION: Eribulin may be a clinically-effective, off-label chemotherapy for recalcitrant osteosarcoma that has failed first- and second-line therapy.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias Óseas/tratamiento farmacológico , Furanos/farmacología , Cetonas/farmacología , Osteosarcoma/tratamiento farmacológico , Tibia/efectos de los fármacos , Adolescente , Animales , Neoplasias Óseas/patología , Humanos , Masculino , Ratones Desnudos , Necrosis , Osteosarcoma/patología , Tibia/patología , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
3.
Anticancer Res ; 41(4): 1883-1893, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33813393

RESUMEN

BACKGROUND/AIM: Hepatocellular carcinoma (HCC) is a highly prevalent disease and treatment is limited. Therefore, development of new therapeutic agents is urgent. The aim of this study was to investigate the in vitro and in vivo anti-cancer effects of Nardostachys jatamansi root extract (NJRE) against HCC and underlying mechanisms involved in such effects. MATERIALS AND METHODS: Effects of NJRE on viability of HCC cell lines were determined by MTT analysis and annexin/PI apoptosis assays. Expression levels of proteins in MAPK and STAT3 pathways and caspase-3 and PARP after treatment with NJRE in HCC cell lines were determined by western blotting. In a syngeneic model using mouse HCC cells Hepa1-6, inhibition of tumor formation after oral administration of NJRE was determined and expression levels of phospho-ERK and phospho-STAT3 in liver tissues were analyzed by immunohistochemical staining. RESULTS: NJRE reduced the activation of STAT3 by inhibiting the expression of ERK and finally attenuated the proliferation of HCC. CONCLUSION: NJRE has anti-cancer effects against HCC. It has potential to be used in the treatment of human HCC.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Nardostachys , Raíces de Plantas , Factor de Transcripción STAT3/metabolismo , Animales , Antineoplásicos Fitogénicos/aislamiento & purificación , Apoptosis/efectos de los fármacos , Carcinoma Hepatocelular/enzimología , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Neoplasias Hepáticas/enzimología , Neoplasias Hepáticas/patología , Masculino , Ratones Endogámicos C57BL , Nardostachys/química , Fosforilación , Raíces de Plantas/química , Transducción de Señal , Carga Tumoral/efectos de los fármacos
4.
Anticancer Res ; 41(4): 1937-1944, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33813399

RESUMEN

BACKGROUND/AIM: To assess the prognostic relevance of volume-based parameters [whole body (wb)-metabolic tumor volume (MTV) and wb-total lesion glycolysis (TLG)] of pretreatment PET/CT in patients with potentially platinum-responsive recurrent ovarian cancer. PATIENTS AND METHODS: This retrospective investigation analyzed 67 patients at first relapse. RESULTS: At univariate analysis, post-relapse survival and overall survival correlated with residual disease after primary surgery (RD) (p=0.015 and 0.049, respectively), time to recurrence (p=0.005 and p=0.0003), number of recurrence sites (p=0.001 and p=0.0005), treatment at recurrence (p=0.044 and 0.043) and wb-MTV (p=0.023 and 0.021) but not with wb-TLG. RD, time to recurrence and number of recurrence sites, but not wb-MTV, were independent prognostic variables for post-relapse survival, and time to recurrence and number of recurrence sites, but not wb-MTV, were independent prognostic factors for overall survival. CONCLUSION: Volume-based parameters of PET/CT are not independent predictors of clinical outcome in potentially platinum-responsive recurrent ovarian cancer.


Asunto(s)
Carcinoma Epitelial de Ovario/diagnóstico , Recurrencia Local de Neoplasia/diagnóstico , Neoplasias Ováricas/diagnóstico , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Carga Tumoral/fisiología , Adulto , Anciano , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/patología , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Fluorodesoxiglucosa F18 , Humanos , Italia , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Compuestos de Platino/uso terapéutico , Valor Predictivo de las Pruebas , Pronóstico , Estudios Retrospectivos , Resultado del Tratamiento , Carga Tumoral/efectos de los fármacos
5.
Int J Mol Sci ; 22(5)2021 Mar 06.
Artículo en Inglés | MEDLINE | ID: mdl-33800754

RESUMEN

The natural isoquinoline alkaloid Berberine (BBR) has been shown to possess several therapeutic effects, including anticancer activity. Different BBR derivatives have been designed and synthesized in order to obtain new compounds with enhanced anticancer efficacy. We previously showed that intraperitoneal (IP) administration of the BBR-derived NAX014 compound was able to counteract HER-2 overexpressing mammary tumors onset and progression in transgenic mice. However, the IP administration was found to induce organ toxicity at doses higher than 2.5 mg/Kg. In this study, we evaluated the effect of intragastric (IG) administration of 20 mg/kg of NAX014 on both safety and anticancer efficacy in HER-2/neu transgenic mice. Furthermore, cancer cell dissemination and migration, tumor cell senescence and immunological changes were examined. Our results demonstrated that IG NAX014 administration delayed the onset of mammary tumors with no negative effects on health and survival. NAX014 reduced HER-2 overexpressing BC cells migration in vitro and the frequency of lung metastasis in HER-2/neu transgenic mice. A statistically significant increase of senescence-associated p16 expression was observed in tumors from NAX014-treated mice, and the induction of cell senescence was observed in HER-2 overexpressing BC cells after in vitro treatment with NAX014. Although NAX014 did not modulate the presence of tumor-infiltrating lymphocytes, the level of circulating TNF-α and VEGF was found to be reduced in NAX014-treated mice. The overall results address the NAX014 compound as potential tool for therapeutic strategies against HER-2 overexpressing breast cancer.


Asunto(s)
Antineoplásicos/uso terapéutico , Alcaloides de Berberina/uso terapéutico , Genes erbB-2 , Neoplasias Mamarias Experimentales/prevención & control , Metástasis de la Neoplasia/prevención & control , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Alcaloides de Berberina/administración & dosificación , Alcaloides de Berberina/química , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/genética , Ratones , Ratones Transgénicos , Estructura Molecular , Metástasis de la Neoplasia/tratamiento farmacológico , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Ratas , Carga Tumoral/efectos de los fármacos
6.
Int J Mol Sci ; 22(6)2021 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-33801911

RESUMEN

Although epoxyeicosatrienoic acid (EET) analogs have performed well in several acute and chronic kidney disease models, targeted delivery of EET analogs to the kidney can be reasonably expected to reduce the level of drug needed to achieve a therapeutic effect and obviate possible side effects. For EET analog kidney-targeted delivery, we conjugated a stable EET analog to folic acid via a PEG-diamine linker. Next, we compared the kidney targeted EET analog, EET-F01, to a well-studied EET analog, EET-A. EET-A or EET-F01 was infused i.v. and plasma and kidney tissue collected. EET-A was detected in the plasma but was undetectable in the kidney. On the other hand, EET-F01 was detected in the plasma and kidney. Experiments were conducted to compare the efficacy of EET-F01 and EET-A for decreasing cisplatin nephrotoxicity. Cisplatin was administered to WKY rats treated with vehicle, EET-A (10 mg/kg i.p.) or EET-F01 (20 mg/kg or 2 mg/kg i.p.). Cisplatin increased kidney injury markers, viz., blood urea nitrogen (BUN), N-acetyl-ß-(D)-glucosaminidase (NAG), kidney injury molecule-1 (KIM-1), and thiobarbituric acid reactive substances (TBARS). EET-F01 was as effective as EET-A in decreasing BUN, NAG, KIM-1, TBARS, and renal histological injury caused by cisplatin. Despite its almost 2×-greater molecular weight compared with EET-A, EET-F01 was comparably effective in decreasing renal injury at a 10-fold w/w lower dose. EET-F01 decreased cisplatin nephrotoxicity by reducing oxidative stress and inflammation. These data demonstrate that EET-F01 targets the kidney, allows for a lower effective dose, and combats cisplatin nephrotoxicity. In conclusion, we have developed a kidney targeted EET analog, EET-F01, that demonstrates excellent potential as a therapeutic for kidney diseases.


Asunto(s)
Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Neoplasias de la Mama/tratamiento farmacológico , Inflamación/prevención & control , Enfermedades Renales/prevención & control , Riñón/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ácido 8,11,14-Eicosatrienoico/química , Ácido 8,11,14-Eicosatrienoico/farmacocinética , Ácido 8,11,14-Eicosatrienoico/farmacología , Animales , Neoplasias de la Mama/patología , Línea Celular Tumoral , Cisplatino , Femenino , Humanos , Inflamación/metabolismo , Riñón/patología , Enfermedades Renales/inducido químicamente , Enfermedades Renales/metabolismo , Masculino , Ratones Desnudos , Ratas Endogámicas WKY , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto/métodos
7.
Int J Mol Sci ; 22(4)2021 Feb 17.
Artículo en Inglés | MEDLINE | ID: mdl-33671258

RESUMEN

We evaluated the abscopal effect of re-implantation of liquid nitrogen-treated tumor-bearing bone grafts and the synergistic effect of anti-PD-1 (programmed death-1) therapy using a bone metastasis model, created by injecting MMT-060562 cells into the bilateral tibiae of 6-8-week-old female C3H mice. After 2 weeks, the lateral tumors were treated by excision, cryotreatment using liquid nitrogen, excision with anti-PD-1 treatment, and cryotreatment with anti-PD-1 treatment. Anti-mouse PD-1 4H2 was injected on days 1, 6, 12, and 18 post-treatment. The mice were euthanized after 3 weeks; the abscopal effect was evaluated by focusing on growth inhibition of the abscopal tumor. The re-implantation of frozen autografts significantly inhibited the growth of the remaining abscopal tumors. However, a more potent abscopal effect was observed in the anti-PD-1 antibody group. The number of CD8+ T cells infiltrating the abscopal tumor and tumor-specific interferon-γ (IFN-γ)-producing spleen cells increased in the liquid nitrogen-treated group compared with those in the excision group, with no significant difference. The number was significantly higher in the anti-PD-1 antibody-treated group than in the non-treated group. Overall, re-implantation of tumor-bearing frozen autograft has an abscopal effect on abscopal tumor growth, although re-implantation of liquid nitrogen-treated bone grafts did not induce a strong T-cell response or tumor-suppressive effect.


Asunto(s)
Autoinjertos/efectos de los fármacos , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/patología , /uso terapéutico , Animales , Neoplasias Óseas/inmunología , Linfocitos T CD8-positivos/inmunología , Carcinogénesis/patología , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Ratones Endogámicos C3H , Metástasis de la Neoplasia , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/metabolismo , Esplenomegalia/patología , Carga Tumoral/efectos de los fármacos
8.
Molecules ; 26(4)2021 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-33670520

RESUMEN

Uncaria tomentosa is a medicinal plant native to Peru that has been traditionally used in the treatment of various inflammatory disorders. In this study, the effectiveness of U. tomentosa as an anti-cancer agent was assessed using the growth and survival of B16-BL6 mouse melanoma cells. B16-BL6 cell cultures treated with both ethanol and phosphate-buffered saline (PBS) extracts of U. tomentosa displayed up to 80% lower levels of growth and increased apoptosis compared to vehicle controls. Treatment with ethanolic extracts of Uncaria tomentosa were much more effective than treatment with aqueous extracts. U. tomentosa was also shown to inhibit B16-BL6 cell growth in C57/bl mice in vivo. Mice injected with both the ethanolic and aqueous extracts of U. tomentosa showed a 59 ± 13% decrease in B16-BL6 tumour weight and a 40 ± 9% decrease in tumour size. Histochemical analysis of the B16-BL6 tumours showed a strong reduction in the Ki-67 cell proliferation marker in U. tomentosa-treated mice and a small, but insignificant increase in terminal transferase dUTP nick labelling (TUNEL) staining. Furthermore, U. tomentosa extracts reduced angiogenic markers and reduced the infiltration of T cells into the tumours. Collectively, the results in this study concluded that U. tomentosa has potent anti-cancer activity that significantly inhibited cancer cells in vitro and in vivo.


Asunto(s)
Apoptosis , Uña de Gato/química , Melanoma Experimental/patología , Animales , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Células 3T3 NIH , Fosforilación/efectos de los fármacos , Extractos Vegetales/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Carga Tumoral/efectos de los fármacos
9.
Nat Cell Biol ; 23(3): 278-291, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33664496

RESUMEN

Activated EGFR signalling drives tumorigenicity in 50% of glioblastoma (GBM). However, EGFR-targeting therapy has proven ineffective in treating patients with GBM, indicating that there is redundant EGFR activation. Circular RNAs are covalently closed RNA transcripts that are involved in various physiological and pathological processes. Herein, we report an additional activation mechanism of EGFR signalling in GBM by an undescribed secretory E-cadherin protein variant (C-E-Cad) encoded by a circular E-cadherin (circ-E-Cad) RNA through multiple-round open reading frame translation. C-E-Cad is overexpressed in GBM and promotes glioma stem cell tumorigenicity. C-E-Cad activates EGFR independent of EGF through association with the EGFR CR2 domain using a unique 14-amino-acid carboxy terminus, thereby maintaining glioma stem cell tumorigenicity. Notably, inhibition of C-E-Cad markedly enhances the antitumour activity of therapeutic anti-EGFR strategies in GBM. Our results uncover a critical role of C-E-Cad in stimulating EGFR signalling and provide a promising approach for treating EGFR-driven GBM.


Asunto(s)
Antígenos CD/metabolismo , Neoplasias Encefálicas/enzimología , Cadherinas/metabolismo , Glioblastoma/enzimología , ARN Circular/metabolismo , Factor de Transcripción STAT3/metabolismo , Animales , Antígenos CD/genética , Antineoplásicos/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Cadherinas/genética , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Glioblastoma/patología , Humanos , Ratones Desnudos , Invasividad Neoplásica , ARN Circular/genética , Factor de Transcripción STAT3/genética , Transducción de Señal , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
11.
Nat Commun ; 12(1): 898, 2021 02 09.
Artículo en Inglés | MEDLINE | ID: mdl-33563973

RESUMEN

Radiation sensitivity varies greatly between tissues. The transcription factor p53 mediates the response to radiation; however, the abundance of p53 protein does not correlate well with the extent of radiosensitivity across tissues. Given recent studies showing that the temporal dynamics of p53 influence the fate of cultured cells in response to irradiation, we set out to determine the dynamic behavior of p53 and its impact on radiation sensitivity in vivo. We find that radiosensitive tissues show prolonged p53 signaling after radiation, while more resistant tissues show transient p53 activation. Sustaining p53 using a small molecule (NMI801) that inhibits Mdm2, a negative regulator of p53, reduced viability in cell culture and suppressed tumor growth. Our work proposes a mechanism for the control of radiation sensitivity and suggests tools to alter the dynamics of p53 to enhance tumor clearance. Similar approaches can be used to enhance killing of cancer cells or reduce toxicity in normal tissues following genotoxic therapies.


Asunto(s)
Tolerancia a Radiación , Proteína p53 Supresora de Tumor/metabolismo , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Humanos , Ratones , Neoplasias/tratamiento farmacológico , Neoplasias/radioterapia , Unión Proteica/efectos de los fármacos , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Tolerancia a Radiación/efectos de los fármacos , Distribución Tisular/efectos de los fármacos , Carga Tumoral/efectos de los fármacos , Proteína p53 Supresora de Tumor/efectos de la radiación , Ensayos Antitumor por Modelo de Xenoinjerto
12.
Carbohydr Polym ; 255: 117370, 2021 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-33436203

RESUMEN

Natural polysaccharides have attracted considerable interests due to diverse biological activities. Succinoglycan is an extracellular polysaccharide produced by most Agrobacterium strains. Here, we confirmed riclin was a typical succinoglycan by NMR and methylation analysis, and investigated the antitumor effects of riclin in sarcoma 180 tumor-bearing mice. The results showed that riclin inhibited the tumor growth significantly as well as cyclophosphamide (CTX). While CTX caused serious damage to spleen structure, riclin increased the spleen index and promoted lymphocytes proliferation in peripheral blood, spleen and lymph nodes. Riclin decreased splenocytes apoptosis as evidenced by alterations of B-cell lymphoma-2 family proteins and Cleaved Caspase-3 protein. Moreover, 1H nuclear magnetic resonance (NMR)-based metabolomics analysis revealed that riclin partially altered the metabolic profiles of splenocytes. In conclusion, riclin is a succinoglycan that performed strong immunogenicity and suppressed sarcoma growth in mice. Succinoglycan riclin could be a potential antitumor agent for functional food and pharmaceutical purpose.


Asunto(s)
Antineoplásicos/farmacología , Regulación Neoplásica de la Expresión Génica , Factores Inmunológicos/farmacología , Linfocitos/efectos de los fármacos , Polisacáridos Bacterianos/farmacología , Sarcoma 180/tratamiento farmacológico , Agrobacterium/química , Animales , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Apoptosis/efectos de los fármacos , Apoptosis/genética , Secuencia de Carbohidratos , Caspasa 3/genética , Caspasa 3/inmunología , Proliferación Celular/efectos de los fármacos , Ciclofosfamida/farmacología , Factores Inmunológicos/química , Factores Inmunológicos/aislamiento & purificación , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/patología , Linfocitos/inmunología , Linfocitos/patología , Masculino , Metaboloma/inmunología , Metilación , Ratones , Ratones Endogámicos C57BL , Polisacáridos Bacterianos/química , Polisacáridos Bacterianos/aislamiento & purificación , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/inmunología , Sarcoma 180/genética , Sarcoma 180/inmunología , Sarcoma 180/patología , Bazo/efectos de los fármacos , Bazo/inmunología , Bazo/patología , Carga Tumoral/efectos de los fármacos
13.
Carbohydr Polym ; 255: 117393, 2021 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-33436222

RESUMEN

In this paper, a novel redox-responsive nanoparticles has been designed for targeted delivery of docetaxel (DTX). Chondroitin sulfate (CS) was used to construct the nanoparticles due to the ability of tumor targeting through binding with CD44 receptor that overexpresses on the surfaces of various tumor cells. A redox-responsive small-molecular DTX prodrug was prepared through modifying with cystamine containing disulfide bonds (Cys-DTX). Then the DTX prodrug was grafted to the CS to construct the amphiphilic polymer (CS-ss-DTX). Further, Cys-DTX/CS-ss-DTX nanoparticles were formed by self-assembly of amphiphilic polymer and incorporation of free Cys-DTX prodrug. This category of nanosized DTX delivery system was expected for not only exhibiting high permeability and cytotoxicity of Cys-DTX prodrug, but also targeting transportation of encapsulated redox-responsive Cys-DTX prodrug. According to results of related researches on physicochemical properties and biological evaluation, the novel redox-responsive Cys-DTX/CS-ss-DTX nanoparticles increased amount of DTX released from the nanoparticles in reductive environment, improved permeability in tumor tissues, enhanced cytotoxicity and decreased side effects compared with free DTX. All of these results showed that this kind of Cys-DTX/CS-ss-DTX nanoparticles were worthy of being expectation in tumor chemotherapy in future.


Asunto(s)
Antineoplásicos/farmacología , Sulfatos de Condroitina/química , Docetaxel/farmacología , Glicoconjugados/farmacología , Melanoma Experimental/tratamiento farmacológico , Profármacos/farmacología , Neoplasias Cutáneas/tratamiento farmacológico , Animales , Antineoplásicos/química , Antineoplásicos/metabolismo , Supervivencia Celular/efectos de los fármacos , Docetaxel/química , Docetaxel/metabolismo , Portadores de Fármacos/síntesis química , Portadores de Fármacos/metabolismo , Portadores de Fármacos/farmacología , Liberación de Fármacos , Femenino , Glicoconjugados/química , Glicoconjugados/metabolismo , Humanos , Células MCF-7 , Melanoma Experimental/metabolismo , Melanoma Experimental/patología , Ratones , Micelas , Nanopartículas/administración & dosificación , Nanopartículas/química , Nanopartículas/ultraestructura , Oxidación-Reducción , Profármacos/química , Profármacos/metabolismo , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Carga Tumoral/efectos de los fármacos
14.
Carbohydr Polym ; 255: 117490, 2021 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-33436250

RESUMEN

To deliver photosensitizers with PEGylated heparin (HP) into tumor cells for photodynamic therapy, we prepared two polyethylene glycol (PEG)-functionalized HP-based polymers conjugated with pyropheophorbide-a (Ppa): a non-GSH-responsive nanoagent (HP-Ppa-mPEG) with the mPEG moiety chemically attached to HP directly; and a GSH-responsive nanoagent (HP-Ppa-SS-mPEG) with the mPEG moiety conjugated to HP via a disulfide linkage. The Ppa-functionalized HP without PEGylation (HP-Ppa) was designed as another control. These amphiphilic polymers could aggregate into nanoparticles. Cellular uptake of three nanoparticles by 4T1 cells led to abundant production of reactive oxygen species after irradiation by a 660 nm laser, inducing cell apoptosis. HP-Ppa-SS-mPEG was found to achieve the highest tumor accumulation, the longest retention time and the best penetration into tumor tissues, resulting in the highest in vivo anticancer efficacy with 94.3 % tumor growth inhibition rate, suggesting that tumor microenvironment-responsive PEGylated HP-based nanomedicines may act as efficient anticancer agents.


Asunto(s)
Antineoplásicos/farmacología , Clorofila/análogos & derivados , Heparina/química , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Fármacos Fotosensibilizantes/farmacología , Microambiente Tumoral/efectos de los fármacos , Animales , Antineoplásicos/síntesis química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Clorofila/química , Femenino , Rayos Láser , Luz , Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Endogámicos BALB C , Nanoconjugados/química , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/síntesis química , Polietilenglicoles/química , Especies Reactivas de Oxígeno/agonistas , Especies Reactivas de Oxígeno/metabolismo , Esferoides Celulares/efectos de los fármacos , Esferoides Celulares/metabolismo , Esferoides Celulares/patología , Resultado del Tratamiento , Carga Tumoral/efectos de los fármacos
15.
Carbohydr Polym ; 255: 117532, 2021 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-33436261

RESUMEN

Aldolase A (ALDOA) facilitated aerobic glycolysis in cancer cells is a potential target in the treatment of hepatocellular carcinoma (HCC). However, only few effective inhibitors of ALDOA have been reported until now. In this research, we found a polysaccharide called HDPS-4II from Holotrichia diomphalia Bates, which can specifically bind to ALDOA with a dissociation constant of 2.86 µM. HDPS-4II with a molecular weight of 19 kDa was a linear triple-helix glucan composed of ɑ-d-1,4-Glcp and ɑ-d-1,6-Glcp in a ratio of 1.0:10.0. HDPS-4II significantly inhibited aldolase enzyme activity, glycolysis, and further inhibited the expression of phosphorylated AMPKα in HCC cells. Through analyzing ALDOA-overexpressing and -knockdown cells, it was confirmed that ALDOA mediated the viability and glycolysis inhibition of HDPS-4II. Moreover, HDPS-4II administration markedly inhibited tumor growth in mice xenografted with HCCs. These findings suggest that HDPS-4II, as an ALDOA antagonist, is a promising remedy in the treatment and prevention of HCC.


Asunto(s)
Antineoplásicos/farmacología , Escarabajos/química , Fructosa-Bifosfato Aldolasa/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glucanos/farmacología , Neoplasias Hepáticas/tratamiento farmacológico , Animales , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Fructosa-Bifosfato Aldolasa/antagonistas & inhibidores , Fructosa-Bifosfato Aldolasa/metabolismo , Glucanos/química , Glucanos/aislamiento & purificación , Glucólisis/efectos de los fármacos , Glucólisis/genética , Células Hep G2 , Hexoquinasa/genética , Hexoquinasa/metabolismo , Humanos , L-Lactato Deshidrogenasa/genética , L-Lactato Deshidrogenasa/metabolismo , Larva/química , Neoplasias Hepáticas/enzimología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Ratones , Piruvato Quinasa/genética , Piruvato Quinasa/metabolismo , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
16.
J Agric Food Chem ; 69(2): 676-685, 2021 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-33406839

RESUMEN

In the present study, the antitumor effects of docosahexaenoic acid-phosphatidylcholine (DHA-PC) and eicosapentanoic acid-phosphatidylcholine (EPA-PC) in Lewis lung cancer mice were investigated. As observed, DHA-PC and EPA-PC obviously inhibited the transplanted tumor growth and the positive expression of Ki67. The metastatic nodules and hematoxylin and eosin (HE) staining of the lung indicated that DHA-PC and EPA-PC suppressed lung metastasis. PPARγ has a key role in cell survival, which may be a target for cancer therapy. Further mechanism research indicated that DHA-PC and EPA-PC significantly enhanced the levels of PPARγ and subsequently downregulated the NF-κB pathway. DHA-PC and EPA-PC accelerate cancer cell apoptosis by decreasing NF-κB-mediated antiapoptotic factors Bcl-2 and Bcl-XL, thereby inhibiting tumor growth. In addition, DHA-PC and EPA-PC significantly decreased the levels of NF-κB-mediated matrix metallopeptidase 9 (MMP9) and heparanase (HPA), which block the extracellular matrix (ECM) degradation, thereby suppressing lung metastasis. These findings suggested that DHA-PC and EPA-PC could be used as food supplements and/or functional ingredients for cancer patients.


Asunto(s)
Ácidos Docosahexaenoicos/administración & dosificación , Ácido Eicosapentaenoico/administración & dosificación , Neoplasias Pulmonares/tratamiento farmacológico , Fosfatidilcolinas/administración & dosificación , Animales , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Ácidos Docosahexaenoicos/análisis , Ácido Eicosapentaenoico/análisis , Femenino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Ratones , Ratones Endogámicos C57BL , FN-kappa B/genética , FN-kappa B/metabolismo , Metástasis de la Neoplasia , PPAR gamma/genética , PPAR gamma/metabolismo , Fosfatidilcolinas/análisis , Carga Tumoral/efectos de los fármacos
17.
Mol Carcinog ; 60(2): 151-163, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33428809

RESUMEN

Regorafenib is approved for patients with unresectable hepatocellular carcinoma (HCC) following sorafenib. However, the effect of regorafenib on HCC metastasis and its mechanism are poorly understood. Here, our data showed that regorafenib significantly restrained the migration, invasion and vasculogenic mimicry (VM) of HCC cells, and downregulated the expression of epithelial-to-mesenchymal transition (EMT)/VM-related molecules. Using RNA-seq and cellular thermal shift assays, we found that inhibitor of differentiation 1 (ID1) was a key target of regorafenib. In HCC tissues, the protein expression of ID1 was positively correlated with EMT and VM formation (CD34- /PAS+ ). Functionally, ID1 knockdown inhibited HCC cell migration, invasion, metastasis, and VM formation in vitro and in vivo, with upregulation of E-cadherin and downregulation of Snail and VE-cadherin. Moreover, Snail overexpression promoted the migration, invasion, and VM formation of ID1 knockdown cells. Snail knockdown reduced the migration, invasion, and VM formation of ID1 overexpression cells. Finally, regorafenib suppressed VM formation and decreased the expression of ID1, VE-cadherin and Snail in HCC PDX model. In conclusion, we manifested that regorafenib distinctly inhibited EMT in HCC cells via targeting ID1, leading to the suppression of cell migration, invasion and VM formation. These findings suggest that regorafenib may be developed as a suitable therapeutic agent for HCC metastasis.


Asunto(s)
Carcinoma Hepatocelular/prevención & control , Movimiento Celular/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Proteína 1 Inhibidora de la Diferenciación/antagonistas & inhibidores , Neoplasias Hepáticas/prevención & control , Neovascularización Patológica/prevención & control , Compuestos de Fenilurea/farmacología , Piridinas/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Animales , Carcinoma Hepatocelular/irrigación sanguínea , Carcinoma Hepatocelular/genética , Línea Celular Tumoral , Movimiento Celular/genética , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células Hep G2 , Humanos , Proteína 1 Inhibidora de la Diferenciación/genética , Proteína 1 Inhibidora de la Diferenciación/metabolismo , Neoplasias Hepáticas/irrigación sanguínea , Neoplasias Hepáticas/genética , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Invasividad Neoplásica , Neovascularización Patológica/genética , Carga Tumoral/efectos de los fármacos , Carga Tumoral/genética
18.
Cancer Invest ; 39(4): 333-348, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33474992

RESUMEN

This study investigates the anticancer potential of methanolic extract of A. subulatum dry fruits (MEAS) in Dalton's Lymphoma Ascites (DLA) cells in vitro and on DLA induced ascitic and solid tumor-bearing mice. MEAS induced apoptosis in DLA cells and MEAS administration effectively reduced tumor burden, and increased life span via modulating pro-inflammatory cytokines and regulating NF-κB pathway. MEAS seemed to be much safer than the standard drug cyclophosphamide, as the latter was associated with adverse effects such as body weight loss, depletion of hemoglobin level and hepatotoxicity, suggesting A. subulatum as a potential nutraceutical against cancer.


Asunto(s)
Amomum , Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Ascitis/tratamiento farmacológico , Linfoma de Células T/tratamiento farmacológico , Extractos Vegetales/farmacología , Amomum/química , Animales , Antineoplásicos Alquilantes/farmacología , Antineoplásicos Fitogénicos/aislamiento & purificación , Ascitis/sangre , Ascitis/patología , Línea Celular Tumoral , Ciclofosfamida/farmacología , Citocinas/sangre , Mediadores de Inflamación/sangre , Mediadores de Inflamación/metabolismo , Linfoma de Células T/sangre , Linfoma de Células T/patología , Masculino , Ratones Endogámicos BALB C , Extractos Vegetales/aislamiento & purificación , Transducción de Señal , Carga Tumoral/efectos de los fármacos
19.
Biochim Biophys Acta Gen Subj ; 1865(3): 129841, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33412224

RESUMEN

BACKGROUND: Triple negative breast cancer (TNBC) is the most aggressive form of breast cancer with limited treatment modalities. It is associated with high propensity of cancer recurrence. METHODS: UV Spectroscopy, FTIR, DLS, Zeta potential, TEM and SEM were employed to characterize nanoparticles. MTT assay, Wound healing assay, SEM, Immunocytochemistry analysis, Western blot, RT-PCR, mammosphere formation assay were employed to study apoptosis, cell migration and stemness. Tumor regression was studied in chick embryo xenograft and BALB/c mice model. RESULTS: Hylaluronic acid engrafted metformin loaded graphene oxide (HA-GO-Met) nanoparticles exhibited an anti-cancer efficacy at much lower dosage as compared to metformin alone. HA-GO-Met nanoparticles induced apoptosis and inhibited cell migration of TNBC cells by targeting miR-10b/PTEN axis via NFkB-p65. Upregulation of PTEN affected pAKT(473) expression that induced apoptosis. Cell migration was inhibited by reduction of pFAK/integrinß1 expressions. Treatment inhibited epithelial mesenchymal transition (EMT) and reduced stemness as evident from the increase in E-cadherin expression, inhibition of mammosphere formation and low expression levels of stemness markers including nanog, oct4 and sox2 as compared to control. Moreover, tumor regression was studied in chick embryo xenograft and BALB/c mice model. HA-GO-Met nanoparticle treatment reduced tumor load and nullified toxicity in peripheral organs imparted by tumor. CONCLUSIONS: HA-GO-Met nanoparticles exhibited an enormous anti-cancer efficacy in TNBC in vitro and in vivo. GENERAL SIGNIFICANCE: HA-GO-Met nanoparticles induced apoptosis and attenuated cell migration in TNBC. It nullified overall toxicity imparted by tumor load. It inhibited EMT and reduced stemness and thereby addressed the issue of cancer recurrence.


Asunto(s)
Antineoplásicos/farmacología , Grafito/química , Receptores de Hialuranos/genética , Ácido Hialurónico/química , Metformina/farmacología , Nanopartículas/química , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Animales , Antineoplásicos/metabolismo , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Embrión de Pollo , Membrana Corioalantoides/efectos de los fármacos , Membrana Corioalantoides/metabolismo , Membrana Corioalantoides/patología , Portadores de Fármacos , Femenino , Quinasa 1 de Adhesión Focal/genética , Quinasa 1 de Adhesión Focal/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Receptores de Hialuranos/metabolismo , Metformina/metabolismo , Ratones , Ratones Endogámicos BALB C , MicroARNs/genética , MicroARNs/metabolismo , Terapia Molecular Dirigida , Nanopartículas/administración & dosificación , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Factor de Transcripción ReIA/genética , Factor de Transcripción ReIA/metabolismo , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
20.
Nat Commun ; 12(1): 653, 2021 01 28.
Artículo en Inglés | MEDLINE | ID: mdl-33510147

RESUMEN

Only a subpopulation of non-small cell lung cancer (NSCLC) patients responds to immunotherapies, highlighting the urgent need to develop therapeutic strategies to improve patient outcome. We develop a chemical positive modulator (HEI3090) of the purinergic P2RX7 receptor that potentiates αPD-1 treatment to effectively control the growth of lung tumors in transplantable and oncogene-induced mouse models and triggers long lasting antitumor immune responses. Mechanistically, the molecule stimulates dendritic P2RX7-expressing cells to generate IL-18 which leads to the production of IFN-γ by Natural Killer and CD4+ T cells within tumors. Combined with immune checkpoint inhibitor, the molecule induces a complete tumor regression in 80% of LLC tumor-bearing mice. Cured mice are also protected against tumor re-challenge due to a CD8-dependent protective response. Hence, combination treatment of small-molecule P2RX7 activator followed by immune checkpoint inhibitor represents a strategy that may be active against NSCLC.


Asunto(s)
Carcinoma Pulmonar de Lewis/terapia , Inmunoterapia/métodos , Receptores Purinérgicos P2X7/inmunología , Bibliotecas de Moléculas Pequeñas/farmacología , Animales , Carcinoma Pulmonar de Lewis/genética , Carcinoma Pulmonar de Lewis/inmunología , Línea Celular Tumoral , Terapia Combinada , Femenino , Células HEK293 , Humanos , Interferón gamma/inmunología , Interferón gamma/metabolismo , Interleucina-18/genética , Interleucina-18/inmunología , Interleucina-18/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Estructura Molecular , Receptores Purinérgicos P2X7/genética , Receptores Purinérgicos P2X7/metabolismo , Bibliotecas de Moléculas Pequeñas/química , Análisis de Supervivencia , Carga Tumoral/efectos de los fármacos , Carga Tumoral/inmunología
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