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1.
Tumour Biol ; 42(2): 1010428319901061, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32013807

RESUMEN

Burkitt lymphoma is a very aggressive B-cell non-Hodgkin lymphoma. Although remarkable progress has been made in the therapeutic scenario for patients with Burkitt lymphoma, search and development of new effective anticancer agents to improve patient outcome and minimize toxicity has become an urgent issue. In this study, the antitumoral activity of Inula viscosa, a traditional herb obtained from plants collected on the Asinara Island, Italy, was evaluated in order to explore potential antineoplastic effects of its metabolites on Burkitt lymphoma. Raji human cell line was treated with increasing Inula viscosa extract concentration for cytotoxicity screening and subsequent establishment of cell cycle arrest and apoptosis. Moreover, gene expression profiles were performed to identify molecular mechanisms involved in the anticancer activities of this medical plant. The Inula viscosa extract exhibited powerful antiproliferative and cytotoxic activities on Raji cell line, showing a dose- and time-dependent decrease in cell viability, obtained by cell cycle arrest in the G2/M phase and an increase in cell apoptosis. The treatment with Inula viscosa caused downregulation of genes involved in cell cycle and proliferation (c-MYC, CCND1) and inhibition of cell apoptosis (BCL2, BCL2L1, BCL11A). The Inula viscosa extract causes strong anticancer effects on Burkitt lymphoma cell line. The molecular mechanisms underlying such antineoplastic activity are based on targeting and downregulation of genes involved in cell cycle and apoptosis. Our data suggest that Inula viscosa natural metabolites should be further exploited as potential antineoplastic agents against Burkitt lymphoma.


Asunto(s)
Linfoma de Burkitt/tratamiento farmacológico , Proliferación Celular/efectos de los fármacos , Inula/química , Proteínas de Neoplasias/genética , Apoptosis/efectos de los fármacos , Linfoma de Burkitt/genética , Linfoma de Burkitt/patología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Extractos Vegetales/química , Extractos Vegetales/farmacología
2.
Life Sci ; 242: 117248, 2020 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-31899224

RESUMEN

Diabetic nephropathy is the most common long-term complication of diabetes mellitus. The Methylglyoxal (MGO) production is mainly by metabolic pathways, such as lipolysis and glycolysis, its increases in the DM enhances oxidative stress and plays a crucial role in the diabetic nephrotic pathogenesis. Phosphocreatine (PCr) can improve lipopolysaccharide, ox-LDL-induced atherosclerosis, and alleviate vascular endothelial cell injury in diabetes. The aim of our present study is to examine the potential role of phosphocreatine (PCr) as a molecule protects against diabetes-induced Kidney Injury in-vitro and in-vivo through ERK/Nrf2/HO-1 signaling pathway. NRK-52E cells treatment with PCr obviously suppressed MGO-induced change of viability, apoptosis, coupled with decreased Bax/Bcl-2ratio, casapse-9 and caspase-3expressions. We determined the generation of reactive oxygen species (ROS) using membrane permeable fluorescent probe DCFH-DA as well as intracellular calcium by flow cytometry. ERK, Nrf2 and HO-1 expressions were determined by Western blot. PCr pretreatment significantly returned the oxidative stress enzymes to normal condition in-vitro and in-vivo. PCr pretreatment significantly reduced apoptosis, calcium and ROS production, induced by MGO, in NRK-52E cells. Moreover, pretreatment with PCr significantly inhibited cleaved caspase-3, cleaved caspase-9 and p-ERK expressions, while increased Nrf-2 and HO-1 expressions. Furthermore, PCr pretreatment significantly decreased p-ERK expression of MGO-induced injury in NRK-52E cells transfected with p-ERK cDNA. In conclusion, the renal protective effect of PCr in-vitro and in-vivo depends on suppressing apoptosis and ROS generation through ERK mediated Nrf-2/HO-1 pathway, suggesting that PCr may be a novel therapeutic candidate for the diabetic nephropathy treatment.


Asunto(s)
Nefropatías Diabéticas/prevención & control , Hemo Oxigenasa (Desciclizante)/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Fosfocreatina/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Western Blotting , Calcio/metabolismo , Línea Celular , Diabetes Mellitus Experimental/complicaciones , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo
3.
Bratisl Lek Listy ; 121(1): 43-50, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31950839

RESUMEN

AIM: Noscapine, a naturally occurring alkaloid obtained from opium poppy, is a microtubule-targeting agent. This study is aimed to investigate the effects of noscapine on human breast cancer cell lines by comparing them with those of tamoxifen and docetaxel. METHODS: MCF-7 and MDA MB-23 cell lines were used to observe the effects of docetaxel, tamoxifen, and noscapine on cell proliferation. For each drug, cell blocks were prepared from cultured cells treated with IC50 dose of each drug and these were examined histologically. The expressions of Ki-67, Bcl-2, BAX, and cyclin-D1 were assessed immunohistochemically. RESULTS: Although noscapine showed cytotoxic effects on both cell lines in a time and dose dependent manner, MDA-MB-231 cells were more susceptible to its effects. Noscapine inhibited MCF-7 and MDA-MB-231 cells proliferation in vitro with IC50 value of 29 µM and 69 µM, respectively, which was comparable with IC50 of tamoxifen (40 µM and 50 µM) and docetaxel (43 nM and 32 nM). Noscapine showed anti-proliferative effects by decreasing Ki-67, cyclin-D1 and apoptotic effects by increasing BAX/Bcl-2 ratio in both breast cancer cells. Its effect was comparable with tamoxifen and docetaxel. CONCLUSION: Noscapine may be a good chemotherapeutic agent for the treatment of breast cancer, especially in estrogen receptor­negative breast cancer (Tab. 2, Fig. 7, Ref. 40).


Asunto(s)
Antineoplásicos , Apoptosis , Neoplasias de la Mama , Noscapina , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Línea Celular Tumoral , Humanos , Células MCF-7 , Noscapina/farmacología , Receptores Estrogénicos , Tamoxifeno
4.
Bratisl Lek Listy ; 121(1): 79-95, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31950844

RESUMEN

AIM: The aim of this review article is to summarize current knowledge about the role of cannabinoids and cannabinoid receptors in tumor disease modulation and to evaluate comprehensively the use of cannabinoids in cancer patients. METHOD: According to the PRISMA protocol, we have included data from a total of 105 articles. RESULTS: Cannabinoids affect cancer progression by three mechanisms. The most important mechanism is the stimulation of autophagy and affecting the signaling pathways leading to apoptosis. The most important mechanism of this process is the accumulation of ceramide. Cannabinoids also stimulate apoptosis by mechanisms independent of autophagy. Other mechanisms by which cannabinoids affect tumor growth are inhibition of tumor angiogenesis, invasiveness, metastasis, and the modulation of the anti-tumor immune response. CONCLUSION: In addition to the symptomatic therapy of cancer patients, the antitumor effects of cannabinoids (whether in monotherapy or in combination with other cancer therapies) have promising potential in the treatment of cancer patients. More clinical trials are needed to demonstrate the antitumor effect of cannabinoids (Tab. 1, Fig. 1, Ref. 167).


Asunto(s)
Cannabinoides , Neoplasias , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Cannabinoides/uso terapéutico , Humanos , Neoplasias/tratamiento farmacológico , Receptores de Cannabinoides
5.
Anticancer Res ; 40(1): 53-66, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31892552

RESUMEN

BACKGROUND/AIM: Medulloblastoma (MB) accounts for ~20% of pediatric malignant central nervous system tumors. Treatment strategies, including surgery, radiation therapy and/or chemotherapy, are effective, but recurrence and metastasis frequently occur. Therefore, novel therapies are required. Herein, the effects of fibroblast growth factor receptor (FGFR) and phosphoinositide 3-kinase (PI3K) inhibitors on MB cells lines were evaluated. MATERIALS AND METHODS: MB cell lines (UW228-3, DAOY, Med8a, D425, D283) were tested for sensitivity to FGFR (AZD4547) and PI3K (BEZ235 and BYL719) inhibitors by viability, cytotoxicity, apoptosis, and proliferation assays. RESULTS: Single treatments with FGFR and PI3K inhibitors decreased viability and proliferation in a dose-dependent pattern in most cell lines. Combinination of the two type of drugs, increased sensitivity, especially of the most resistant cell line UW228-3. CONCLUSION: Combination treatments with FGFR and PI3K inhibitors were superior to single treatments with FGFR and PI3K inhibitors, especially with BEZ235, for MB cell lines.


Asunto(s)
Meduloblastoma/metabolismo , Fosfatidilinositol 3-Quinasa/metabolismo , Receptores de Factores de Crecimiento de Fibroblastos/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Caspasa 3/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Humanos , Meduloblastoma/patología , Inhibidores de Proteínas Quinasas/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto
6.
Anticancer Res ; 40(1): 67-73, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31892553

RESUMEN

BACKGROUND/AIM: Aberrant expression of the SEI1 oncogene has been prevalently found in a variety of human cancers, including oral squamous cell carcinoma (OSCC). Recent studies have shown that cisplatin up-regulates the expression of SEI1 in breast and bladder cancer cells, thus inhibiting apoptosis and cell death in these cells. In the present study, we investigated the impact of cisplatin on the expression of SEI1 in OSCC cells. MATERIALS AND METHODS: Four OSCC cell lines, CAL27, SCC4, SCC15, and SCC22A were treated with cisplatin and 5-fluorouracil, and changes in SEI1 expression in these cells were evaluated using quantitative Reverse Transcription-Polymerase Chain Reaction (qRT-PCR) analyses. RESULTS: Cisplatin significantly induced SEI1 expression in the tested OSCC cells. Contrarily, cisplatin treatment did not affect the expression of gankyrin and BMI1, two oncogenes frequently overexpressed in a coordinate manner with SEI1 in OSCC. Additionally, 5-fluorouracil did not bring about any detectable changes in SEI1 expression in these cells. CONCLUSION: Cisplatin-induced up-regulation of SEI1 expression in OSCC is specific, and such induction could underlie the development of resistance to cisplatin in OSCC.


Asunto(s)
Carcinoma de Células Escamosas/genética , Cisplatino/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neoplasias de la Boca/genética , Oncogenes , Factores de Transcripción/genética , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos , Fluorouracilo/farmacología , Humanos
7.
Anticancer Res ; 40(1): 121-132, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31892560

RESUMEN

BACKGROUND/AIM: Pancreatic neuroendocrine tumors (pNETs) are rare pancreatic neoplasms, and therapeutic options for pNETs are limited. Metformin is an anti-hypoglycemic drug that appears to have anticancer effects. However, little is known about the effect of metformin on pNETs. In this study, we investigated the anti-proliferative effect of metformin on a human pNET cell line. MATERIALS AND METHODS: The anti-proliferative properties of metformin were evaluated in QGP-1 and NCI-H727 cells using a cell counting kit-8 assay. Xenograft mouse models were used to assess the tumor effect in vivo. RESULTS: Metformin inhibited the proliferation and anti-tumor growth of QGP-1 cells, accompanied by their arrest during the cell cycle at the G0/G1 phase. Immunohistochemical analysis of tumor tissues revealed down-regulation of cyclin D1 and proliferating cell nuclear antigen in the metformin-treated group. Additionally, metformin induced apoptosis, and the expression of survivin and claspin were decreased in metformin-treated QGP-1 cells according to the apoptosis array. Furthermore, the angiogenic related protein TIMP-1 was down-regulated, and its miRNA expression was altered by metformin in QGP-1 cells. CONCLUSION: Taken together, our study demonstrated the therapeutic potential of metformin and provides molecular mechanistic insights into its anti-tumoral effect on pNETs. This study is the first one describing anti-tumoral effects in pNETs.


Asunto(s)
Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Metformina/farmacología , Biomarcadores , Carcinoma Neuroendocrino/tratamiento farmacológico , Carcinoma Neuroendocrino/metabolismo , Carcinoma Neuroendocrino/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , MicroARNs/genética , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/metabolismo , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
8.
Anticancer Res ; 40(1): 133-141, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31892561

RESUMEN

BACKGROUND/AIM: Aberrant expression of the BMI1 oncogene has been prevalently found in a variety of human cancers, including cervical cancer. Recent studies have shown that PTC209, a specific BMI1 inhibitor, exhibits high potency in inhibiting the growth of colon, breast, oral cancer cells and cancer-initiating cells, indicative of its chemotherapeutic potential. In the current study, we evaluated the inhibitory abilities of PTC209 in cervical cancer cells. MATERIALS AND METHODS: Three cervical cell lines, C33A, HeLa, and SiHa were treated with PTC209. The impacts of PTC209 on BMI1 were investigated using quantitative reverse-transcription PCR assay (qRT-PCR) and western blotting; changes in cell viability, cell cycle distribution, and apoptosis were assessed using cell viability testing, colony formation assay and flow cytometry analyses, respectively. RESULTS: PTC209 exhibited considerably high short-term and long-term cytotoxicities in all tested cervical cancer cell lines regardless of their HPV infection status, TP53 and pRb statuses. PTC209 significantly downregulated the expression of BMI1 in cervical cancer cell lines, and such downregulation led to G0/G1 arrest (p<0.05). Moreover, PTC209 drove more cells into apoptosis (p<0.05). CONCLUSION: PTC209 (BMI1-targeting agents, in general) represents a novel chemotherapeutic agent with potential in cervical cancer therapy.


Asunto(s)
Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Complejo Represivo Polycomb 1/antagonistas & inhibidores , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular/efectos de los fármacos , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Complejo Represivo Polycomb 1/genética , Complejo Represivo Polycomb 1/metabolismo , Neoplasias del Cuello Uterino/metabolismo , Neoplasias del Cuello Uterino/patología
9.
J Agric Food Chem ; 68(2): 633-641, 2020 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-31891488

RESUMEN

As typical perfluorinated compounds (PFCs), perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) have been detected in various environmental media and their toxic effects have been extensively studied. Nevertheless, it remains unclear how PFCs cause cell apoptosis in healthy hepatocytes by inducing oxidative stress at the subcellular and molecular levels. In this study, the apoptotic pathways induced by PFOA and PFOS were explored. Besides, the effects of PFCs on the structure and function of lysozyme (LYZ) were investigated. After PFOA and PFOS exposure, the cell membrane and mitochondrial membrane potential were damaged. Further, PFOA and PFOS increased intracellular Ca2+ levels to 174.41 ± 1.70 and 158.91 ± 5.94%, respectively. Ultimately, caspase-3 was activated, causing cell apoptosis. As an indirect antioxidant enzyme, the molecular structure of LYZ was destroyed after interacting with PFOA and PFOS. Both PFOA and PFOS bound to the active center of LYZ, leading to the decrease of LYZ activity to 91.26 ± 0.78 and 76.01 ± 4.86%, respectively. This study demonstrates that PFOA and PFOS inhibit LYZ function, which can reduce the body's ability to resist oxidative stress, and then lead to mitochondria-mediated apoptosis.


Asunto(s)
Ácidos Alcanesulfónicos/farmacología , Apoptosis/efectos de los fármacos , Caprilatos/farmacología , Fluorocarburos/farmacología , Hepatocitos/efectos de los fármacos , Calcio/metabolismo , Caspasa 3/metabolismo , Línea Celular , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Hepatocitos/citología , Hepatocitos/metabolismo , Humanos , Estrés Oxidativo/efectos de los fármacos
10.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 51(1): 13-17, 2020 Jan.
Artículo en Chino | MEDLINE | ID: mdl-31950783

RESUMEN

Objective: To investigate the effects of Akkermansia muciniphila ( A. muciniphila) on the proliferation, apoptosis and insulin secretion of rat pancreatic islet cell tumor cells (INS-1). Methods: INS-1 cells were divided into three groups, normal, repair, and protect groups, and subsequently every group was subjected with A. muciniphila metabolites, live A. muciniphilaorpasteurized A. muciniphila for 48 h. A group that did not treat with anything was set as blank control. After intervention, the cell viability was determined by MTT method, the insulin secretion level stimulated by glucose was determined by ELISA, the expressions of the genes involved in insulin secretion and apoptosis were tested by qRT-PCR, and the expression of apoptosis related protein Bax was evaluated by Western blot. Results: There was no significant change in INS-1 cell morphology after co-incubation with 3 types of A. Muciniphila interventions for 48 h. The proliferative activity of INS-1 cells was decreased in the repair group that treated with live A. muciniphila than that of control ( P<0.005). A. muciniphila intervention had no effect on insulin secretion in INS-1 cells in normal, repair or protection group ( P>0.05). A. muciniphila secretions promoted the expression of glucose transporter 2 ( Glut2) in 3 groups and the expression of glucokinase ( GCK) in repair group ( P<0.05). The expression of Baxof the INS-1 cell in the normal group was decreased after intervented with 3 kinds of A. muciniphila intervention materials ( P<0.001).The expression of Bax gene of the INS-1 cell in the repair group that treated with dead A. muciniphilawas decreased ( P<0.05). The expression of Bax protein of INS-1 cells that treated with A. muciniphila interventions was decreased. Conclusion: A. muciniphila can promote the expression of insulin secretion-related genes in INS-1 cells, inhibit the expression of apoptotic genes and apoptosis protein Bax.This research provides a new direction for applying A. muciniphila in improving type 2 diabetes.


Asunto(s)
Adenoma de Células de los Islotes Pancreáticos , Apoptosis , Diabetes Mellitus Tipo 2 , Secreción de Insulina , Probióticos , Verrucomicrobia , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular , Regulación de la Expresión Génica/efectos de los fármacos , Glucosa/farmacología , Secreción de Insulina/efectos de los fármacos , Ratas , Verrucomicrobia/fisiología
11.
J Photochem Photobiol B ; 203: 111748, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31918235

RESUMEN

Nanotechnology is an emerged field to develop the plant mediated metal based nanodrugs by green method. In this current study, the zinc oxide metal based nanoparticles were developed using (Clausena lansium (Lour.) Skeels) Peel aqueous extracts and zinc nitrate. The C.L extract zinc nanoparticleswere indicated by the sharp peak seen at 350 nm utilizing the Ultraviolet-Visible spectroscopy (UV-Vis). The high peaks indicate the presence of phytochemicals and its functional groups in ZnONPs were studied by the Fourier Transform Infrared Spectroscopy (FT-IR). The X-Ray Diffraction analysis (XRD) explores the pattern and structure of ZnONPs as spherical and base-centered monoclinic crystalline shapes. The C.L extract with Zn nanoparticles were spherical in nature and the size of the synthesized particles were about 28.42 nm respectively. The autophagy (Beclin-1, LC3-I, LC3-II and ATG4B) and apoptotic (Bax, Bcl-2 and Caspase-3) proteins were regulated by the treatment with ZnONPs in SH-SY5Y neuroblastoma cells. The DNA loss or damage was occurred in the ZnONPs treatment and it was performed using Comet assay. The ZnONPs treatment generates the ROS in the cells and decreased its stability and viability. Addition of NAC prevents ROS in the cultured SH-SY5Y cells and prevents the cells from the apoptosis. We concluded that the ZnONPs potentially kills the neuroblastoma cells by producing the intracellular ROS.


Asunto(s)
Antineoplásicos/farmacología , Autofagia/efectos de los fármacos , Nanopartículas del Metal/química , Óxido de Zinc/química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Beclina-1/metabolismo , Caspasa 3/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Clausena/química , Clausena/metabolismo , Daño del ADN/efectos de los fármacos , Tecnología Química Verde , Humanos , Nanopartículas del Metal/toxicidad , Neuroblastoma/metabolismo , Neuroblastoma/patología , Extractos Vegetales/química , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Especies Reactivas de Oxígeno/metabolismo
12.
J Photochem Photobiol B ; 203: 111773, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31931385

RESUMEN

Glioma is the prime cause of cancer allied mortality in adolescent people and it accounts about 80% of all malignant tumours. Eugenol is a major bioactive constituent present in the essential oils with numerous pharmacological benefits including nueroprotective activity. The major drawback of eugenol is its extreme volatile property and oxygen sensitivity therefore we increased the efficacy of drug; eugenol by encapsulating with chitosan polymer. Eugenol loaded chitosan polymer (EuCs) was characterized using FTIR, XRD, SEM, HR-TEM analysis and the encapsulation, drug release efficacy was assessed at in vitro condition. The induction of autophagy and anticancer efficacy of EuCs on glioma cells was evaluated with rat C6 glioma cells using MTT assay, acridine orange staining, immunocytochemical analysis of NFκß protein expression and FLOW cytometric analysis. The anti-metastatic property of Eu-CS was assessed by immunoblotting and RT-PCR analysis of epithelial mesenchymal transition protein expression in EuCs treated rat C6 glioma cells. Our characterization analysis proves that EuCs possess essential physical and functional properties of copolymer to be utilized as a drug. Further the MTT analysis and AO staining confirms even in the presence of oncogenic inducer and autophagic inhibitors, EuCs exhibits apoptotic potency on rat C6 glioma cells. The result of immunocytochemical studies depicts the inhibition of NFκß protein expression and flow cytometry studies confirm apoptosis induction by EuCs. The inhibition of metastasis by EuCs was proven by the decrease in epithelial mesenchymal transition protein expression in Eu-Cs treated rat C6 glioma cells. Over all our results authentically confirms eugenol loaded chitosan nanopolymer persuasively induces apoptosis and inhibits metastasis in rat C6 glioma cells.


Asunto(s)
Antineoplásicos/química , Apoptosis/efectos de los fármacos , Quitosano/química , Eugenol/química , Metaloproteinasa 9 de la Matriz/metabolismo , Nanoestructuras/química , Transducción de Señal/efectos de los fármacos , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Portadores de Fármacos/química , Eugenol/farmacología , Glioma/metabolismo , Glioma/patología , FN-kappa B/metabolismo , Ratas , Activador de Plasminógeno de Tipo Uroquinasa/metabolismo
13.
J Photochem Photobiol B ; 203: 111778, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31931389

RESUMEN

In the last decade, gold nanoparticles have emerged as promising agents for in vitro bio-sensing and in vivo cancer theranostics. However, different investigations have reported widely varying cytotoxicity and uptake efficiency of gold nanoparticles depending upon their size. Therefore, more extensive studies are needed to standardize these biological effects as a function of size on a particular cell line. In addition, to obtain robust confirmation on the correlation of a size to biological effect, thorough mechanistic study must also be performed. In this study, the size dependent biological activities of gold nanoparticles on osteosarcoma cells is investigated towards exploring their potential theranostic application in bone cancer, for which very scarce literature reports are available. Tris-assisted citrate based method was optimized to synthesize stable gold naoparticles of 40-60 nm sizes. Nanoparticles were characterized through UV-Vis spectroscopy, field emission scanning electron microscope (FESEM) and dynamic light scattering (DLS). Increasing concentrations of gold nanoparticles (AuNPs) of 46 nm size, enhanced the rate of reactive oxygen species (ROS)-induced apoptosis in MG63 cells by disrupting their mitochondrial membrane potential. Considerably higher cell death was observed for 46 and 60 nm AuNPs compared to 38 nm at all concentrations of 200, 400 and 800 ng/mL. Further, molecular signatures of cellular apoptosis under nanoparticle treatment were optically assessed through surface enhanced Raman scattering (SERS). A significant Raman enhancement in cancer cells under treatment of larger gold nanoparticles (46 and 60 nm) at fixed wavelength of 785 nm and laser power of 8.0 mW was evident. In corroboration with molecular biology techniques, SERS observation confirmed the size-dependent apoptotic phenomena in osteosarcoma cells under treatment of gold nanoparticles. Study demonstrates a facile, non-active targeting approach for detection of size-dependent AuNP-induced apoptosis in osteosarcoma cells through label-free SERS method.


Asunto(s)
Apoptosis/efectos de los fármacos , Oro/química , Nanopartículas del Metal/toxicidad , Caspasa 3/metabolismo , Línea Celular Tumoral , Dispersión Dinámica de Luz , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Nanopartículas del Metal/química , Microscopía Fluorescente , Osteosarcoma/metabolismo , Osteosarcoma/patología , Tamaño de la Partícula , Especies Reactivas de Oxígeno/metabolismo , Espectrometría Raman
14.
Life Sci ; 244: 117280, 2020 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-31926239

RESUMEN

AIMS: Recently, chemoresistance has been recognized as an obstacle in the treatment of gastric cancer (GC). The aim of this study was to investigate the biological functions and underlying mechanisms of propofol in GC chemoresistance. MAIN METHODS: CCK-8 assay, flow cytometry and immunofluorescent staining were performed to assess the IC50 concentration, cell apoptosis and autophagy activity of cisplatin in both GC chemosensitive cells (SGC7901) and chemoresistant cells (SGC7901/CDDP). The expression pattern of MALAT1 in GC cells was detected by qRT-PCR. The shRNAs and overexpressing plasmids were employed for the loss or gain-of-function. Dual-luciferase reporter assay was subjected to verify the binding relationship between MALAT1 and miR-30e. Besides, ATG5 mRNA and protein levels were determined using qRT-PCR and western blot analysis. Furthermore, GC xenograft mice model was established to validate the in vitro findings. KEY FINDINGS: Chemoresistant GC cells presented higher IC50 of cisplatin, increased autophagy activity and stronger expression of MALAT1. The application of propofol promoted cell apoptosis and reduced the activity of autophagy through downregulating MALAT1. Silencing of MALAT1 inhibited chemo-induced autophagy, whereas MALAT1 overexpression promoted autophagy in GC cells. Mechanistic researches demonstrated that MALAT1 could bind with miR-30e to regulate ATG5 expression, thus causing the suppression of autophagy. In vivo GC xenograft model treated with both propofol and cisplatin also showed significantly decreased tumor size and weight, which was enhanced by knockdown of MALAT1. SIGNIFICANCE: Altogether, our study revealed a novel mechanism of propofol of lncRNA MALAT1/miR-30e/ATG5 mediated autophagy-related chemoresistance in GC, casting new lights on the understanding of propofol.


Asunto(s)
MicroARNs/genética , Propofol/metabolismo , ARN Largo no Codificante/metabolismo , Animales , Apoptosis/efectos de los fármacos , Autofagia/genética , Proteína 5 Relacionada con la Autofagia/genética , Proteína 5 Relacionada con la Autofagia/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , China , Cisplatino/metabolismo , Cisplatino/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Ratones , Ratones Desnudos , MicroARNs/metabolismo , Propofol/farmacología , ARN Largo no Codificante/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
15.
Life Sci ; 244: 117299, 2020 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-31953157

RESUMEN

AIMS: Notch signaling is highly implicated in several cancers and chemoresistance. Therefore, Notch-targeted therapies might be beneficial in enhancing chemotherapeutic effect and cancer regression. This study aimed to investigate implication of Notch in development and progression of solid Ehrlich carcinoma (SEC) and enhancement of anticancer effect of cisplatin (CIS) by addition of thymoquinone (TQ) and pentoxifylline (PTX) through modulation of Notch. MAIN METHODS: SEC was induced in mice as model for mammary carcinoma by s.c. injection of 1 × 106 Ehrlich cells into back of the mice. On 12th day, solid tumor was developed and mice were divided into seven groups; tumor control, early CIS (ECIS), ECIS + ETQ, ECIS + ETQ + EPTX, late CIS (LCIS), LCIS + LTQ, and LCIS + LTQ + LPTX. Early treatment was started on 12th day, whereas late treatment was begun on 19th day from tumor inoculation. At the endpoint, samples were collected for detection of Notch1, Hes1, Jagged1, ß-catenin, TNF-α, IL-6, IFN-γ, IL-2, VEGF, apoptosis, CD4, and CD8. KEY FINDINGS: Adding PTX and TQ to CIS significantly reduced Notch1, Hes1, Jagged1, ß-catenin, TNF-α, IL-6, IFN-γ, and VEGF with increment in IL-2, CD4, CD8, and apoptotic cells. Moreover, early treated groups showed remarkable attenuation in tumor growth and the relevant parameters compared to their counterpart later groups. SIGNIFICANCE: Addition of PTX with TQ to CIS showed a synergistic chemotherapeutic action and induced better oncostatic effect mainly through Notch suppression. Consequently, shutting Notch could be of great interest in promoting chemosensetivity and cancer control.


Asunto(s)
Benzoquinonas/farmacología , Pentoxifilina/farmacología , Receptores Notch/metabolismo , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Apoptosis/efectos de los fármacos , Benzoquinonas/metabolismo , Carcinoma de Ehrlich/tratamiento farmacológico , Carcinoma de Ehrlich/metabolismo , Cisplatino/metabolismo , Cisplatino/farmacología , Femenino , Ratones , Pentoxifilina/metabolismo , Receptor Notch1/metabolismo , Transducción de Señal/efectos de los fármacos
16.
Life Sci ; 244: 117332, 2020 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-31962133

RESUMEN

AIMS: It has been demonstrated that reduced expression of alpha7 nicotinic acetylcholine receptor (α7nAChR) led to reduced chemotherapeutic drugs resistance in various cancer cells. However, whether small interfering RNA (siRNA) mediated knockdown of α7nAChR can reduce sorafenib (SOR) resistance in HCC cells remains to be determined. MATERIALS AND METHODS: The effects of α7nAChR-siRNA in combination with SOR treatment was analyzed in human (HepG2) and mouse (Hepa 1-6) HCC cell lines. The MTT, DAPI staining and flow cytometry assays were applied to measure the cell viability, apoptosis and cell cycle progression of the cells. Also, the changes in the mRNA and protein levels of the α7nAChR were measured by quantitative real-time PCR and western blot analysis, respectively. KEY FINDINGS: The results revealed that SOR increased both mRNA and protein levels of α7nAChR in HCC cells. Treatment with α7nAChR-siRNA abolished these effects. Also, SOR treatment in combination with α7nAChR-siRNA significantly sensitizes HCC cells to SOR cytotoxicity. This combination therapy significantly induced HCC cells apoptosis compared to SOR alone. SIGNIFICANCE: These experimental results indicate that knockdown of α7nAChR by siRNA increased the SOR antitumor activity of HCC cells and suggests that this additive combination is a promising drug candidate for HCC therapy.


Asunto(s)
Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Sorafenib/farmacología , Receptor Nicotínico de Acetilcolina alfa 7/genética , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Resistencia a Antineoplásicos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Ratones , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/genética , Receptor Nicotínico de Acetilcolina alfa 7/metabolismo
17.
Nat Commun ; 11(1): 567, 2020 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-31992692

RESUMEN

Since the discovery of metal nanoparticles (NPs) in the 1960s, unknown toxicity, cost and the ethical hurdles of research in humans have hindered the translation of these NPs to clinical use. In this work, we demonstrate that Pt NPs with protein coronas are generated in vivo in human blood when a patient is treated with cisplatin. These self-assembled Pt NPs form rapidly, accumulate in tumors, and remain in the body for an extended period of time. Additionally, the Pt NPs are safe for use in humans and can act as anti-cancer agents to inhibit chemotherapy-resistant tumor growth by consuming intracellular glutathione and activating apoptosis. The tumor inhibitory activity is greatly amplified when the Pt NPs are loaded in vitro with the chemotherapeutic drug, daunorubicin, and the formulation is effective even in daunorubicin-resistant models. These in vivo-generated metal NPs represent a biocompatible drug delivery platform for chemotherapy resistant tumor treatment.


Asunto(s)
Antineoplásicos/sangre , Antineoplásicos/farmacología , Nanopartículas del Metal/química , Platino (Metal)/sangre , Platino (Metal)/farmacología , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Cisplatino/farmacología , Daunorrubicina/farmacología , Sistemas de Liberación de Medicamentos , Tolerancia a Medicamentos , Femenino , Glutatión/metabolismo , Células Hep G2 , Humanos , Células K562 , Glomérulos Renales/efectos de los fármacos , Glomérulos Renales/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Desnudos , Tamaño de la Partícula , Corona de Proteínas , Factores de Tiempo , Ensayos Antitumor por Modelo de Xenoinjerto , Pez Cebra
18.
Anal Bioanal Chem ; 412(1): 149-158, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31897564

RESUMEN

HSP70 is a powerful antiapoptotic protein that can block the extrinsic and intrinsic pathways of apoptosis. The present study describes a rapid, sensitive, and inexpensive system using luciferase as a reporter for the functional analysis of apoptotic compounds. For this approach, the co-transformation of Escherichia coli cells was performed with two expression vectors containing Hsp70 and firefly luciferase. It was found that the luciferase inactivated by heat treatment (40-46 °C for 10 min) was approximately reactivated at room temperature and regained 70% of its initial activity before heat inactivation after 60 min. The results show that the reactivation of thermally inactivated luciferase was inhibited in living cells by treatment with VER-155008 and pifitrin-µ as Hsp70 inhibitors, with half-maximal inhibitory concentration of 124 and 384 µM, respectively. The sensitivity of this method for detecting VER-155008 and pifitrin-µ was about 8 and 25 µM, respectively. Also, this reporter system showed no response to doxorubicin and dactinomycin, which bind to DNA, and we used these anticancer compounds as control compounds. Therefore, for the first time, a rapid and simple real-time system using luciferase as a reporter is introduced for the screening of apoptosis-inducing compounds based on suppression of Hsp70 in E. coli cells.


Asunto(s)
Apoptosis/efectos de los fármacos , Genes Reporteros , Proteínas HSP70 de Choque Térmico/antagonistas & inhibidores , Luciferasas de Luciérnaga/genética , Dactinomicina/farmacología , Relación Dosis-Respuesta a Droga , Doxorrubicina/farmacología , Evaluación Preclínica de Medicamentos , Escherichia coli/genética , Proteínas HSP70 de Choque Térmico/genética
19.
Eur J Med Chem ; 188: 111988, 2020 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-31901746

RESUMEN

In connection with our continued research to generate new aza-fused heteroaromatic chemical scaffolds, we developed a highly atom-economical three-component route to novel 3,4-dihydropyrrolo[1,2-a]pyrazine ring skeleton multi-functionalized on the pyrazine unit. This [4+1+1] annulation approach led us to gain access to a new N-fused bicyclic chemical space having two distinctive functional groups (heteroaryl and aroyl) in a trans manner. Investigation of anticancer activity of the synthesized compounds and their derivatives revealed that (3R*,4S*)-3-(4-bromophenyl)-4-(4-fluorobenzoyl)-2-(2-oxo-2-phenylethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2-ium bromide (3h) has potent anticancer activity. 3h significantly inhibited cell viability in prostate cancer cells (PC-3) and breast cancer cells (MCF-7) with IC50 value of 1.18 ± 0.05 µM and 1.95 ± 0.04 µM, respectively. In addition, 3h strongly reduced cell migration in a dose dependent manner, and induced apoptosis via caspase-3 activation and cleavage of PARP in PC-3 and MCF-7 cells. Our results in this study imply that 3h can be a potential anticancer agent against prostate cancer and breast cancer.


Asunto(s)
Antineoplásicos/farmacología , Pirazinas/farmacología , Pirroles/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Caspasa 3/metabolismo , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Poli(ADP-Ribosa) Polimerasas/metabolismo , Pirazinas/síntesis química , Pirazinas/química , Pirroles/síntesis química , Pirroles/química
20.
Toxicol Lett ; 322: 77-86, 2020 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-31931077

RESUMEN

Failure of all-trans-retinal (atRAL) clearance contributes to retina degeneration. However, whether autophagy can be activated by excess atRAL accumulation in retinal pigment epithelial (RPE) cells is not known. This study showed that atRAL provoked mitochondria-associated reactive oxygen species (ROS) production, activated the nuclear factor (erythroid-derived 2)-like 2 and apoptosis in a human RPE cell line, ARPE-19 cells. Moreover, we found that autophagic flux was functionally activated after atRAL treatment. The antioxidant N-acetylcysteine attenuated the expression of autophagy markers, suggesting that ROS triggered atRAL-activated autophagy. In addition, autophagic cell death was observed in atRAL-treated RPE cells, while inhibition of autophagy with 3-methyladenine or LC3, Beclin1, p62 silencing ameliorated atRAL-induced cytotoxicity. Suppression of autophagy quenched mitochondrial ROS and inhibited HO-1 and γ-GCSh expression, indicating that atRAL-activated autophagy enhances intracellular oxidative stress, thereby promoting RPE cell apoptosis. Furthermore, we found that inhibiting endoplasmic reticulum (ER) stress suppressed atRAL-induced mitochondrial ROS generation, subsequently attenuated autophagy and apoptosis in RPE cells. Taken together, these results suggest that atRAL-induced oxidative stress and ER stress modulate autophagy, which may contribute to RPE degeneration. There may be positive feedback regulatory mechanisms between atRAL-induced oxidative stress and autophagy or ER stress.


Asunto(s)
Autofagia/efectos de los fármacos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Epitelio Pigmentado de la Retina/efectos de los fármacos , Vitamina A/toxicidad , Apoptosis/efectos de los fármacos , Proteínas Relacionadas con la Autofagia/genética , Proteínas Relacionadas con la Autofagia/metabolismo , Línea Celular , Células Epiteliales/metabolismo , Células Epiteliales/patología , Humanos , Mitocondrias/metabolismo , Mitocondrias/patología , Especies Reactivas de Oxígeno/metabolismo , Epitelio Pigmentado de la Retina/metabolismo , Epitelio Pigmentado de la Retina/patología , Transducción de Señal
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