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1.
Bol. latinoam. Caribe plantas med. aromát ; 18(5): 480-491, sept. 2019. ilus, tab
Artigo em Inglês | LILACS | ID: biblio-1008273

RESUMO

In the present study, we investigated the antiproliferative activity of essential oil from leaves of Melissa officinalis L. grown in Southern Bosnia and Herzegovina. In vitro evaluation of antiproliferative activity of the M. officinalis essential oil was carried out on three human tumor cell lines: MCF-7, NCI-H460 and MOLT-4 by MTT assay. M. officinalis essential oil was characterized by high percentage of monoterpenes (77,5%), followed by the sesquiterpene fraction (14,5%) and aliphatic compounds (2,2%). The main constituents of the essential oil of M. officinalis are citral (47,2%), caryophyllene oxide (10,2%), citronellal (5,4%), geraniol (6,6%), geranyl acetate (4,1%) and ß- caryophyllene (3,8%). The essential oil showed significant antiproliferative activity against three cancer cell lines, MOLT-4, MCF-7, and NCI-H460 cells, with GI50 values of <5, 6±2 and 31±17 µg/mL, respectively. The results revealed that M. officinalis L. essential oil has a potential as anticancer therapeutic agent.


En el presente estudio, investigamos la actividad antiproliferativa del aceite esencial de las hojas de Melissa officinalis L. cultivadas en el sur de Bosnia y Herzegovina. La evaluación in vitro de la actividad antiproliferativa del aceite esencial de M. officinalis se llevó a cabo en tres líneas celulares de tumores humanos: MCF-7, NCI-H460 y MOLT-4 utilizando el ensayo de MTT. El aceite esencial de M. officinalis se caracterizó por un alto porcentaje de monoterpenos (77,5%), seguido de la fracción sesquiterpénica (14,5%) y compuestos alifáticos (2,2%). Los principales constituyentes del aceite esencial de M. officinalis fueron citral (47,2%), óxido de cariofileno (10,2%), citronelal (5,4%), geraniol (6,6%), acetato de geranilo (4, 1%), y ß-cariofileno (3,8%). El aceite esencial mostró una actividad antiproliferativa significativa contra las líneas celulares de cáncer MOLT-4, MCF-7 y NCI-H460, con valores GI50 de <5, 6±2 y 31±17 µg/mL, respectivamente. Los resultados revelaron que el aceite esencial de M. officinalis L. tiene potencial como agente terapéutico contra el cáncer.


Assuntos
Óleos Voláteis/farmacologia , Melissa , Antineoplásicos/farmacologia , Sesquiterpenos/análise , Técnicas In Vitro , Óleos Voláteis/química , Células Tumorais Cultivadas , Folhas de Planta , Monoterpenos/análise , Linhagem Celular Tumoral/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cromatografia Gasosa-Espectrometria de Massas , Antineoplásicos/química
2.
Toxicol Lett ; 315: 1-8, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31421153

RESUMO

Arsenic trioxide (As2O3) has been used clinically for the treatment of acute promyelocytic leukemia and some solid tumors. However, the mechanisms of its anti-tumor effects are still elusive. Angiogenesis is a key process for tumor initiation, and increasing evidence has supported the role of anti-angiogenesis caused by arsenic in tumor suppression, although the detailed mechanism is not well understood. In the present study, we found that As2O3 significantly inhibited the angiogenesis of human umbilical vein endothelial cells (HUVECs) in vitro, and this was mediated by the upregulation of FoxO3a. Knockdown of FoxO3a could restore the angiogenic ability of HUVECs. Moreover, vascular endothelial cell-specific knockout of FoxO3a in mice could disrupt the anti-angiogenesis effect of As2O3 and endow the tumors with resistance to As2O3 treatments. Our results revealed a new mechanism by which As2O3 suppresses angiogenesis and tumor growth.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/uso terapêutico , Trióxido de Arsênio/farmacologia , Trióxido de Arsênio/uso terapêutico , Proteína Forkhead Box O3/efeitos dos fármacos , Leucemia Promielocítica Aguda/tratamento farmacológico , Regulação para Cima/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Veias Umbilicais/efeitos dos fármacos
3.
Toxicol Lett ; 315: 77-86, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31470059

RESUMO

T-2 toxin is a major pollutant in crops and feedstuffs. Due to its high toxicity in a variety of organisms, T-2 toxin is of great concern as a threat to humans and to animal breeding. Overexpression of CYP1A1 may contribute to carcinogenesis, and CYP1A1 may be a promising target for the prevention and treatment of human malignancies. Therefore, it is essential to understand the regulatory mechanism by which T-2 toxin induces CYP1A1 expression in human cells. In this study, we confirmed that T-2 toxin (100 ng/mL) induced the expression of CYP1A1 in HepG2 cells through NRF1 and Sp1 bound to the promoter instead of through the well-recognized Aromatic hydrocarbon receptors (AhR). In cells treated with T-2 toxin, Sp1, but not NRF1, was significantly upregulated. However, T-2 toxin apparently promoted the interaction between NRF1 and Sp1 proteins, as revealed by IP analysis. Furthermore, in T-2 toxin-treated HepG2 cells, nuclear translocation of NRF1 was enhanced, while knockdown of Sp1 ablated NRF1 nuclear enrichment. Our results revealed that the upregulation of CYP1A1 by T-2 toxin in HepG2 cells depended on enhanced interaction between Sp1 and NRF1. This finding suggests the tumorigenic features of T-2 toxin might be related to the CYP1A1, which provides new insights to understand the toxicological effect of T-2 toxin.


Assuntos
Citocromo P-450 CYP1A1/efeitos dos fármacos , Citocromo P-450 CYP1A1/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Fator 1 Relacionado a NF-E2/genética , Fator de Transcrição Sp1/genética , Toxina T-2/toxicidade , Regulação para Cima/efeitos dos fármacos , Carcinoma/fisiopatologia , Linhagem Celular Tumoral/efeitos dos fármacos , Linhagem Celular Tumoral/metabolismo , Pesquisas com Embriões , Regulação Enzimológica da Expressão Gênica , Humanos , Rim , Neoplasias Hepáticas/fisiopatologia , Fator 1 Relacionado a NF-E2/efeitos dos fármacos , Fator 1 Relacionado a NF-E2/metabolismo , Fator de Transcrição Sp1/efeitos dos fármacos , Fator de Transcrição Sp1/metabolismo
4.
Biol Res ; 52(1): 37, 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31319879

RESUMO

BACKGROUND: Berberine (BBR), a compound extracted from a variety of medicinal herbs, has been shown multiple pharmacological effects against cancer cells of different origins. Cisplatin (DDP) is known as an effective chemotherapeutic agent against cancer by inducing DNA damage and cell apoptosis. However, the effect of the combined used of BBR and DDP on cell necroptosis in ovarian cancer has not been reported. METHODS: OVCAR3 and three patient-derived primary ovarian cancer cell lines (POCCLs) were chosen as the experimental objects. To determine the potential anti-cancer activity of BBR and DDP in combination, we firstly treated OVCAR3 and POCCLs cells with BBR and/or DDP. The cell viability of OVCAR3 and POCCLs with treatment of BBR or DDP for different hours was measured by CCK-8 assay. Flow cytometry was used to analyze cell cycle distribution and changes in apoptotic cells after treatment with BBR and/or DDP. The morphological changes of OVCAR3 cells were observed by using Transmission electron microscopy (TEM) analysis. Proliferation, apoptosis and necroptosis related markers of OVCAR3 and POCCLs with treatment of BBR or DDP were measured by RT-qPCR, western blotting and immunofluorescence assay. RESULTS: Our results demonstrated that BBR significantly inhibited the proliferation of OVCAR3 and primary ovarian cancer cells in a dose- and time-dependent manner. The combination treatment of BBR and DDP had a prominent inhibitory effect on cancer cell growth and induced G0/G1 cell cycle arrest. TEM revealed that the majority of cells after BBR or DDP treatment had an increasing tendency of typical apoptotic and necrotic cell death morphology. Besides, BBR and DDP inhibited the expression of PCNA and Ki67 and enhanced the expression and activation of Caspase-3, Caspase-8, RIPK3 and MLKL. CONCLUSION: This study proposed that the combination therapy of BBR and DDP markedly enhanced more ovarian cancer cell death by inducing apoptosis and necroptosis, which may improve the anticancer effect of chemotherapy drugs. The apoptosis involved the caspase-dependent pathway, while the necroptosis involved the activation of the RIPK3-MLKL pathway. We hope our findings might provide a new insight for the potential of BBR as a therapeutic agent in the treatment of ovarian cancer.


Assuntos
Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Berberina/uso terapêutico , Cisplatino/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Berberina/farmacologia , Caspases , Linhagem Celular Tumoral/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Necrose
5.
Int. j. morphol ; 37(2): 584-591, June 2019. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1002262

RESUMO

Following the success of the highly active antiretroviral therapy, the potential of multidrug combination regimen for the management of cancer is intensely researched. The anticancer effects of curcumin on some human cell lines have been documented. Lopinavir is a FDA approved protease inhibitor with known apoptotic activities. Dysregulated apoptosis is important for the initiation of cancer while angiogenesis is required for cancer growth and development, this study therefore investigated the effects of the combination of lopinavir and curcumin on cell viability, apoptosis and the mRNA expression levels of key apoptotic and angiogenic genes; BAX, BCL2 and VEGF165b in two human cervical cell lines; human squamous cell carcinoma cells - uterine cervix (HCS-2) and transformed normal human cervical cells (NCE16IIA). The two human cervical cell lines were treated with physiologically relevant concentrations of the agents for 120 h following which BAX, BCL2 and VEGF165b mRNA expression were determined by Real Time qPCR. The Acridine Orange staining for the morphological evaluation of apoptotic cells was also performed. The combination of lopinavir and curcumin up-regulated pro-apoptotic BAX and antiangiogenic VEGF165b but down-regulated the mRNA levels of anti-apoptotic BCL2 mRNA in the human squamous cell carcinoma (HCS-2) cells only. The fold changes were statistically significant. Micrographs from Acridine Orange staining showed characteristic evidence of apoptosis in the human squamous cell carcinoma (HCS-2) cells only. The findings reported here suggest that the combination of curcumin and the FDA approved drug-lopinavir modulate the apoptotic and angiogenic pathway towards the inhibition of cervical cancer.


Tras el éxito de la terapia antirretroviral altamente activa, se investiga intensamente el potencial del régimen de combinación de múltiples fármacos para el tratamiento del cáncer. Se han documentado los efectos anticancerígenos de la curcumina en algunas líneas celulares humanas. Lopinavir es un inhibidor de proteasa aprobado por la FDA con actividades apoptóticas conocidas. La apoptosis disrregulada es importante para el inicio del cáncer, mientras que la angiogénesis es necesaria para el crecimiento y desarrollo del cáncer. Por lo tanto, este estudio investigó los efectos de la combinación de lopinavir y curcumina sobre la viabilidad celular, la apoptosis y los niveles de expresión del ARNm de genes apoptóticos y angiogénicos clave: BAX, BCL2 y VEGF165b en dos líneas celulares cervicales humanas; células de carcinoma de células escamosas humanas: cérvix uterino (HCS-2) y células cervicales humanas transformadas (NCE16IIA). Las dos líneas celulares cervicales humanas se trataron con concentraciones fisiológicamente relevantes de los agentes durante 120 horas, después de lo cual la expresión de ARNm de BAX, BCL2 y VEGF165b se determinó mediante qPCR en tiempo real. También se realizó la tinción con naranja de acridina para la evaluación morfológica de células apoptóticas. La combinación de lopinavir y curcumina reguló incrementando BAX proapoptósicos y VEGF165b antiangiogénicos, pero reguló a la baja los niveles de ARNm del BCL2 antiapoptótico en células de carcinoma de células escamosas humanas (HCS-2) únicamente. Los cambios en el pliegue fueron estadísticamente significativos. Las micrografías de la tinción con naranja de acridina mostraron evidencia característica de apoptosis solo en las células del carcinoma de células escamosas humanas (HCS-2). Los hallazgos reportados aquí sugieren que la combinación de curcumina y el fármaco aprobado por la FDA lopinavir modulan la vía apoptótica y angiogénica hacia la inhibición del cáncer cervical.


Assuntos
Humanos , Feminino , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias do Colo do Útero/tratamento farmacológico , Curcumina/farmacologia , Lopinavir/farmacologia , Antineoplásicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/genética , Proteína X Associada a bcl-2/efeitos dos fármacos , Proteína X Associada a bcl-2/genética , Reação em Cadeia da Polimerase em Tempo Real
6.
Planta Med ; 85(13): 1088-1097, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31216579

RESUMO

As part of our search for new cytotoxic and antimicrobial natural products from endolichenic fungi, 19 compounds including 1 new 10-member lactone (2: ), 1 new polyacetylene glycoside (3: ), 1 new brasilane-type sesquiterpenoid glycoside (4: ), and 2 isobenzofuran-1(3H)-one derivatives (5: and 6: ) were isolated from the solid culture of the endolichenic fungus Hypoxylon fuscum. Their structures were unambiguously elucidated by NMR spectroscopic data, MS, ECD (electronic circular dichroism) calculation, and chemical methods. The cytotoxic effects on K562, SW480, and HEPG2 cell lines and the antimicrobial activity against Bacillus subtilis, Staphylococcus aureus, Escherichia coli, and Candida albicans were assessed. Compounds 1, 2: , and 5: exhibited moderate cytotoxicity against K562, SW480, and HEPG2 cell lines while compounds 1, 9: , and 11: displayed weak antibacterial activity against S. aureus.


Assuntos
Citotoxinas/isolamento & purificação , Xylariales/metabolismo , Anti-Infecciosos/isolamento & purificação , Anti-Infecciosos/farmacologia , Bacillus subtilis/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Linhagem Celular Tumoral/efeitos dos fármacos , Dicroísmo Circular , Citotoxinas/farmacologia , Escherichia coli/efeitos dos fármacos , Células Hep G2/efeitos dos fármacos , Humanos , Células K562/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Staphylococcus aureus/efeitos dos fármacos , Xylariales/química
7.
Planta Med ; 85(11-12): 965-972, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31250411

RESUMO

Three previously undescribed cardenolides, acovenosigenin A 3-O-α-L-acofriopyranoside (1: ), 14-anhydroacovenosigenin A 3-O-[ß-D-glucopyranosyl-(1″→4')-O-α-L-acofriopyranoside] (2: ), and 14-anhydroacovenosigenin A 3-O-[ß-D-glucopyranosyl-(1″→4')-O-α-L-acovenopyranoside] (3: ), together with the two already known ones, 14-anhydrodigitoxigenin 3-O-ß-D-glucopyranoside (4: ) and acospectoside A (5: ), were isolated from the leaves of Acokanthera oblongifolia. The influence of cardenolides 1:  - 3: and acovenoside A (found in the Acokanthera genus) on three cancer cell lines (HT29, HCT116, and AGS) was also investigated. The most promising results, in comparison with oxaliplatin, were obtained for compound 1: , which was found to be highly cytotoxic for all tested cell lines, HT29 (IC50 = 63.49 nM), HCT116 (IC50 = 67.35 nM), and AGS (IC50 = 80.92 nM). Unfortunately, 1: also showed similar toxicity towards normal lymphocytes (IC50 = 98.03 nM).


Assuntos
Apocynaceae/química , Cardenolídeos/isolamento & purificação , Citotoxinas/isolamento & purificação , Folhas de Planta/química , Cardenolídeos/farmacologia , Linhagem Celular Tumoral/efeitos dos fármacos , Citotoxinas/farmacologia , Humanos , Linfócitos/efeitos dos fármacos
8.
Life Sci ; 231: 116586, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31220528

RESUMO

AIMS: Lipocalin 2 (Lcn2/NGAL) belongs to lipocalin superfamily with diverse functions. The precise function of Lcn2, particularly in cancer development, remains to be elucidated yet. In an attempt to knockout of Lcn2 expression by CRISPR/Cas 9 technology in a highly aggressive and invasive prostate cancer cell line and to evaluate the combination therapy with cisplatin (CDDP), this study was conducted. MAIN METHODS: Control CRISPR/Cas9 plasmid and homology-directed repair plasmid or validated human Lcn2 CRISPR/Cas9 KO plasmids were co-transfected into PC3 cells using fugene HD transfection reagent. The stable cells were selected in the presence of puromycin. Correspondingly, knock out of Lcn2 was evaluated by RT-PCR, ELISA, and immunocytochemistry. PC3-Scr (control) and Lcn2-KO (PC3 cells in which lcn2 has been knocked out) were treated with or without cisplatin (CDDP). Cell proliferative ability was measured by WST-1 and colony-formation assays. Apoptosis was evaluated by DAPI staining, in situ cell death detection (TUNEL) assay, and cell death detection ELISA plus methods. The migration capabilities were studied by wound healing/scratch and transwell assays. KEY FINDINGS: Lcn2 knock out in a highly aggressive and invasive cancer cell like PC3 decreased cell proliferation and increased the sensitivity of CDDP. Conspicuously, loss of Lcn2 expression effectively enhanced CDDP-induced apoptosis in PC3 cells. Lcn2 knock out by CRISPR/Cas9 technology decreased the cell migration capacity of PC3 cells as well. SIGNIFICANCE: Lcn2 not only is a valuable and useful biomarker for diagnosis and prognosis of prostate cancer but also and more importantly is a potential novel emerging therapeutic target.


Assuntos
Cisplatino/farmacologia , Lipocalina-2/genética , Lipocalina-2/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Apoptose/efeitos dos fármacos , Sistemas CRISPR-Cas , Linhagem Celular Tumoral/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Técnicas de Inativação de Genes/métodos , Humanos , Masculino , Células PC-3 , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Transdução de Sinais
9.
Microbiol Immunol ; 63(6): 213-222, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31106894

RESUMO

Hinokitiol, a component of the essential oil isolated from Cupressaceae, possesses antibacterial and antifungal activities and has been used in oral care products. In this study, the antibacterial activities of hinokitiol toward various oral, nasal and nasopharyngeal pathogenic bacteria, including Streptococcus mutans, Streptococcus sobrinus, Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Prevotella intermedia, Fusobacterium nucleatum, methicillin-resistant and -susceptible Staphylococcus aureus, antibiotic-resistant and -susceptible Streptococcus pneumoniae, and Streptococcus pyogenes were examined. Growth of all these bacterial strains was significantly inhibited by hinokitiol, minimal inhibitory concentrations of hinokitiol against S. mutans, S. sobrinus, P. gingivalis, P. intermedia, A. actinomycetemcomitans, F. nucleatum, methicillin-resistant S. aureus, methicillin-susceptible S. aureus, antibiotic-resistant S. pneumoniae isolates, antibiotic-susceptible S. pneumoniae, and S. pyogenes being 0.3, 1.0, 1.0, 30, 0.5, 50, 50, 30, 0.3-1.0, 0.5, and 0.3 µg/mL, respectively. Additionally, with the exception of P. gingivalis, hinokitiol exerted bactericidal effects against all bacterial strains 1 hr after exposure. Hinokitiol did not display any significant cytotoxicity toward the human gingival epithelial cell line Ca9-22, pharyngeal epithelial cell line Detroit 562, human umbilical vein endothelial cells, or human gingival fibroblasts, with the exception of treatment with 500 µg/mL hinokitiol, which decreased numbers of viable Ca9-22 cells and gingival fibroblasts by 13% and 12%, respectively. These results suggest that hinokitiol exhibits antibacterial activity against a broad spectrum of pathogenic bacteria and has low cytotoxicity towards human epithelial cells.


Assuntos
Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Monoterpenos/farmacologia , Boca/microbiologia , Tropolona/análogos & derivados , Aggregatibacter actinomycetemcomitans/efeitos dos fármacos , Bactérias/classificação , Linhagem Celular Tumoral/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Fusobacterium nucleatum/efeitos dos fármacos , Humanos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Porphyromonas gingivalis/efeitos dos fármacos , Prevotella intermedia/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Streptococcus mutans/efeitos dos fármacos , Streptococcus pneumoniae/efeitos dos fármacos , Streptococcus pyogenes/efeitos dos fármacos , Streptococcus sobrinus/efeitos dos fármacos , Tropolona/farmacologia
10.
Mar Drugs ; 17(5)2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31052228

RESUMO

BACKGROUND: Fucoidans are interesting for potential usage in ophthalmology, and especially age-related macular degeneration. However, fucoidans from different species may vary in their effects. Here, we compare fucoidans from five algal species in terms of oxidative stress protection and vascular endothelial growth factor (VEGF) interference in ocular cells. METHODS: Brown algae (Fucus vesiculosus, Fucus distichus subsp. evanescens, Fucus serratus, Laminaria digitata, Saccharina latissima) were harvested and fucoidans isolated by hot-water extraction. Fucoidans were tested in several concentrations (1, 10, 50, and 100 µg/mL). Effects were measured on a uveal melanoma cell line (OMM-1) (oxidative stress), retinal pigment epithelium (RPE) cell line ARPE19 (oxidative stress and VEGF), and primary RPE cells (VEGF). Oxidative stress was induced by H2O2 or tert-Butyl hydroperoxide (TBHP). Cell viability was investigated with methyl thiazolyl tetrazolium (MTT or MTS) assay, and VEGF secretion with ELISA. Affinity to VEGF was determined by a competitive binding assay. RESULTS: All fucoidans protected OMM-1 from oxidative stress. However, in ARPE19, only fucoidan from Saccharina latissima was protective. The affinity to VEGF of all fucoidans was stronger than that of heparin, and all reduced VEGF secretion in ARPE19. In primary RPE, only the fucoidan from Saccharina latissima was effective. CONCLUSION: Among the fucoidans from five different species, Saccharina latissima displayed the most promising results concerning oxidative stress protection and reduction of VEGF secretion.


Assuntos
Estresse Oxidativo/efeitos dos fármacos , Polissacarídeos/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Técnicas de Cultura de Células , Linhagem Celular Tumoral/efeitos dos fármacos , Sobrevivência Celular , Olho , Heparina/farmacologia , Humanos , Peróxido de Hidrogênio/farmacologia , Feófitas/química , Polissacarídeos/farmacocinética , Epitélio Pigmentado da Retina/efeitos dos fármacos , Suínos , terc-Butil Hidroperóxido/farmacologia
11.
Life Sci ; 227: 212-223, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30928407

RESUMO

AIMS: 3-Bromopyruvate (3-BP), an alkylating agent and a glycolytic inhibitor, is a promising anticancer agent, which can be efficient also against multidrug-resistant cancer cells. The aim of this study was to examine how 3-BP affects the survival and mobility of rat (MAT-LyLu and AT-2) and human (DU-145 and PC-3) metastatic prostate cancer cell lines. MAIN METHODS: Cytotoxicity was estimated with Neutral Red. Cell mobility was analyzed by time-lapse microscopic monitoring of trajectories of individual cells at 5-min intervals for 6h. ATP was estimated with luciferin/luciferase and glutathione (GSH) with o-phthalaldehyde. Actin cytoskeleton was visualized with phalloidin conjugated with Atto-488. KEY FINDINGS: All metastatic prostate cell lines studied were very sensitive to 3-BP (IC50 of 4-26µM). 3-Bromopyruvate drastically reduced cell movement even at concentrations of 5-10µM after 1h treatment. This compound depleted also cellular ATP and GSH, and disrupted actin cytoskeleton. SIGNIFICANCE: The data obtained suggest that 3-BP can potentially be useful for treatment of metastatic prostate cancer and, especially, be efficient in limiting metastasis.


Assuntos
Neoplasias da Próstata/tratamento farmacológico , Piruvatos/farmacologia , Citoesqueleto de Actina/efeitos dos fármacos , Trifosfato de Adenosina/análise , Animais , Linhagem Celular , Linhagem Celular Tumoral/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Glutationa/análise , Humanos , Masculino , Invasividade Neoplásica , Próstata/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Ratos
12.
Cell Biol Int ; 43(6): 642-650, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30958600

RESUMO

Most traditional cytotoxic chemotherapeutic agents have poor aqueous solubility and significant toxicity. Hence, there is a need to develop molecule-targeted drugs. Programmed death-ligand 1 (PD-L1) is associated with the prognosis of several cancer types, and blockade of PD-1/PD-L1 signaling increases the amplitude of anti-tumor immunity. In the present study, we investigated the effects of JQ1, a bromodomain and extraterminal-bromodomain inhibitor, on cell growth, and messenger RNA (mRNA) and protein levels of PD-L1 in renal cell carcinoma primary culture cells, and prostate, liver, and lung cancer cell lines. The results of the cell counting kit-8 assay suggested that JQ1 inhibits cell growth in a dose-dependent manner. The mRNA and protein levels of PD-L1 decreased in the primary culture of JQ1-treated renal carcinoma, prostate cancer, liver cancer, and lung cancer cell lines. In addition, the mRNA level of PD-L2 also decreased in the JQ1-treated cells. Overall, JQ1 might be a potential anti-tumor agent.


Assuntos
Azepinas/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Carcinoma de Células Renais/metabolismo , Neoplasias/tratamento farmacológico , Triazóis/farmacologia , Azepinas/metabolismo , Antígeno B7-H1/biossíntese , Antígeno B7-H1/genética , Carcinoma de Células Renais/genética , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Cultura Primária de Células , RNA Mensageiro , Transdução de Sinais/efeitos dos fármacos , Triazóis/metabolismo
13.
Med Sci Monit ; 25: 2852-2858, 2019 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-30997898

RESUMO

BACKGROUND We examined the anticancer potential of anthecotulide against SK-MEL-24 malignant melanoma cells. The apoptotic and autophagic effects of anthecotulide were also investigated. MATERIAL AND METHODS The cell viability of SK-MEL-24 human malignant melanoma cells was evaluated by WST-1 assay. Fluorescence microscopy using acridine orange and ethidium bromide staining, as well as Western blot analysis, were used to study apoptotic effects induced by anthecotulide. Autophagy was assessed by Western blot analysis and fluorescence microscopy. Effects of anthecotulide on cell cycle progression were analyzed by flow cytometry. RESULTS The results revealed that anthecotulide exerts significant growth-inhibitory effects on SK-MEL-24 cells. The IC50 of anthecotulide against the SK-MEL-24 cells was found to be 10 µM. However, the anticancer effects against the normal cells were minimal (IC50; 100 µM). Investigation of the underlying mechanism revealed that anthecotulide prompts apoptotic cell death of the SK-MEL-24 cells, which was linked with increased expression of Bax and decreased expression of Bcl-2. It also triggered concentration-dependent activation of caspase 3 and 9. Anthecotulide induced autophagy in the SK-MEL-24 cells, which was associated with upregulation of LC3 II and Beclin-1 expression. Anthecotulide also halted the SK-MEL-24 cells at S-phase of the cell cycle and downregulated the expression of Cyclin B1. However, the expression of p27 was upregulated. CONCLUSIONS These results indicate anthecotulide is a potent lead molecule for the treatment of melanoma. In vivo and other related experiments are warranted to further assess this promising drug candidate.


Assuntos
Lactonas/farmacologia , Melanoma/tratamento farmacológico , Sesquiterpenos/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Caspases/efeitos dos fármacos , Caspases/metabolismo , Ciclo Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Melanoma/metabolismo , NF-kappa B/efeitos dos fármacos , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos
14.
Med Sci Monit ; 25: 2935-2942, 2019 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-31005958

RESUMO

BACKGROUND Thyroid cancer causes considerable mortality and morbidity across the globe. Owing to the unavailability of biomarkers and the adverse effects of existing drugs, there is an urgent need to develop efficient chemotherapy for the treatment of thyroid cancers. Plants have served as exceptional source of drugs for the treatment of lethal diseases. The purpose of this study was to evaluate the anticancer effects of ferruginol against thyroid cancer cells. MATERIAL AND METHODS We monitored the cell proliferation rate using 3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was detected using 4',6-diamidino-2-phenylindole (DAPI), acridine orange/ethidium bromide (AO/EB), and annexin V/propidium iodide (PI) staining. Reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) levels were examined by fluorescence microscopy. Protein expressed was examined by western blotting. RESULTS We found that ferruginol exerted potent antiproliferative action against thyroid cancer cells, and an IC50 of 12 µM was observed for ferruginol against the MDA-T32 cell line. The toxic effects of ferruginol were less pronounced against normal cells. The anticancer effects of ferruginol were likely due to the induction of apoptosis which was also associated with upregulation of Bax and downregulation of Bcl-2. Ferruginol also caused ROS mediated alterations in the MMP of MDA-T32 cells. In MDA-T32 cells, ferruginol might also block the MAPK and PI3K/AKT signaling pathway, which is believed to be an important therapeutic target of anticancer drugs. CONCLUSIONS In conclusion, in view of the results of this study, it might be suggested that ferruginol might serve as an essential lead molecule for the treatment of thyroid cancer provided further in-depth studies especially studying ferruginol toxicological as well as in vivo studies are needed.


Assuntos
Diterpenos de Abietano/farmacologia , Neoplasias da Glândula Tireoide/tratamento farmacológico , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , China , Diterpenos/metabolismo , Diterpenos/farmacologia , Diterpenos de Abietano/metabolismo , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Membranas Mitocondriais/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosfatidilinositol 3-Quinases/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Extratos Vegetais/farmacologia , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
15.
Planta Med ; 85(6): 513-518, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30822815

RESUMO

The ability of certain triterpenoid saponins to modulate the endosomal release during the process of endocytosis and to ensure a nontoxic and efficient transfection recently led to an exceptional interest in the field of nonviral gene delivery. In vitro and in vivo studies demonstrated promising results in terms of tumor growth inhibition after the delivery of a suicide gene such as saporin and dianthin. With that, the question arises which structural features are necessary or advantageous to achieve an effective endosomal escape. Former studies described certain important characteristics a potent saponin should have. Particularly SA1641 (Gypsophila paniculata) and SO1861 (Saponaria officinalis) played an utmost important role to get a first insight into the structure-activity relationship. However, a number of issues such as the purpose of functional groups on the aglycon and the substitution of sugars and their modification remain unsolved and their value needs to be specified. By conducting a screening of several diverse saponins in terms of their transfection improving ability, we aimed to examine these questions in more detail and get a better understanding of the relevant features. The transfection of Neuro-2A-cells with GFP-DNA containing peptide-based nanoplexes provided a reliable method in order to compare the activity of the saponins. With that, we were able to provide new and essential insights regarding the structure-activity relationship of transfection-modulating saponins and give an idea of how a highly potent saponin for future gene therapies may look like.


Assuntos
Técnicas de Transferência de Genes , Saponinas/farmacologia , Transfecção , Animais , Linhagem Celular Tumoral/efeitos dos fármacos , Endossomos/efeitos dos fármacos , Camundongos , Nanoestruturas , Saponinas/química , Relação Estrutura-Atividade , Transfecção/métodos
16.
Nat Commun ; 10(1): 1023, 2019 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-30833574

RESUMO

Diffuse intrinsic pontine glioma (DIPG) is an incurable pediatric brain tumor, with approximately 25% of DIPGs harboring activating ACVR1 mutations that commonly co-associate with H3.1K27M mutations. Here we show that in vitro expression of ACVR1 R206H with and without H3.1K27M upregulates mesenchymal markers and activates Stat3 signaling. In vivo expression of ACVR1 R206H or G328V with H3.1K27M and p53 deletion induces glioma-like lesions but is not sufficient for full gliomagenesis. However, in combination with PDGFA signaling, ACVR1 R206H and H3.1K27M significantly decrease survival and increase tumor incidence. Treatment of ACVR1 R206H mutant DIPGs with exogenous Noggin or the ACVR1 inhibitor LDN212854 significantly prolongs survival, with human ACVR1 mutant DIPG cell lines also being sensitive to LDN212854 treatment. Together, our results demonstrate that ACVR1 R206H and H3.1K27M promote tumor initiation, accelerate gliomagenesis, promote a mesenchymal profile partly due to Stat3 activation, and identify LDN212854 as a promising compound to treat DIPG.


Assuntos
Receptores de Ativinas Tipo I/metabolismo , Astrocitoma/metabolismo , Neoplasias do Tronco Encefálico/metabolismo , Genoma Humano/genética , Glioma/metabolismo , Histonas/metabolismo , Receptores de Ativinas Tipo I/genética , Animais , Astrocitoma/tratamento farmacológico , Astrocitoma/genética , Astrocitoma/patologia , Neoplasias do Tronco Encefálico/tratamento farmacológico , Neoplasias do Tronco Encefálico/genética , Neoplasias do Tronco Encefálico/patologia , Proteínas de Transporte/farmacologia , Linhagem Celular Tumoral/efeitos dos fármacos , Proliferação de Células , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/genética , Glioma/tratamento farmacológico , Glioma/genética , Glioma/patologia , Histonas/genética , Humanos , Camundongos , Mutação , Fator de Crescimento Derivado de Plaquetas/metabolismo , Pirazóis/farmacologia , Pirimidinas/farmacologia , Quinolinas/farmacologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais
17.
Int J Gynaecol Obstet ; 145(2): 225-232, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30828803

RESUMO

OBJECTIVE: To examine the cytotoxicity of epigenetic drugs independently and in combination with chemotherapy on ovarian cancer cells Caov-3, and to investigate their ability to acquire chemoresistance in omental microenvironments and whether epigenetic drugs can counteract this chemoresistance. METHODS: A pilot study was conducted in Cooper University Hospital, NJ, USA from August 1 to October 31, 2017, among women undergoing surgeries for uterine and ovarian cancer. Cytotoxicity assays using IC50 values of epigenetic drugs and paclitaxel and cisplatin were performed on Caov-3. Omental adipose-derived stem cells (OASCs) were isolated from omentum with/without metastases. Caov-3 was cultured with OASCs' conditioned medium and subjected to different drugs. Cell viability and secretome was measured using MTT and Elisa, respectively. RESULTS: Three women met the eligibility criteria and were included in the study. Epigenetic drugs alone or in combination with chemotherapy showed 85%-94% increased cytotoxicity against Caov-3 (P≤0.005). Metastatic OASCs conditioned medium showed up to 27-fold increase in tumorigenic factors and promoted chemoresistance (28%-35%; P < 0.050) against chemotherapy. Epigenetic therapy resulted in up to a 40-fold reversal in this chemoresistance. CONCLUSION: Epigenetic therapies could have an important role in treating a subgroup of ovarian cancer patients that demonstrate resistance to first-line chemotherapy.


Assuntos
Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/farmacologia , Neoplasias Uterinas/tratamento farmacológico , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Omento , Projetos Piloto
18.
Nat Commun ; 10(1): 1033, 2019 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-30833575

RESUMO

Taxanes are a family of natural products with a broad spectrum of anticancer activity. This activity is mediated by interaction with the taxane site of beta-tubulin, leading to microtubule stabilization and cell death. Although widely used in the treatment of breast cancer and other malignancies, existing taxane-based therapies including paclitaxel and the second-generation docetaxel are currently limited by severe adverse effects and dose-limiting toxicity. To discover taxane site modulators, we employ a computational binding site similarity screen of > 14,000 drug-like pockets from PDB, revealing an unexpected similarity between the estrogen receptor and the beta-tubulin taxane binding pocket. Evaluation of nine selective estrogen receptor modulators (SERMs) via cellular and biochemical assays confirms taxane site interaction, microtubule stabilization, and cell proliferation inhibition. Our study demonstrates that SERMs can modulate microtubule assembly and raises the possibility of an estrogen receptor-independent mechanism for inhibiting cell proliferation.


Assuntos
Antineoplásicos/química , Hidrocarbonetos Aromáticos com Pontes/química , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Moduladores Seletivos de Receptor Estrogênico/química , Moduladores Seletivos de Receptor Estrogênico/metabolismo , Taxoides/química , Taxoides/farmacologia , Moduladores de Tubulina/química , Moduladores de Tubulina/metabolismo , Tubulina (Proteína)/química , Antineoplásicos/farmacologia , Sítios de Ligação , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Ligantes , Proteínas dos Microtúbulos/efeitos dos fármacos , Modelos Moleculares , Paclitaxel/farmacologia , Tubulina (Proteína)/efeitos dos fármacos , Microambiente Tumoral
19.
World J Microbiol Biotechnol ; 35(3): 41, 2019 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-30762133

RESUMO

L-asparaginase is an enzyme capable of hydrolyzing the substrate asparagine in aspartic acid and ammonia. Due to this mechanism of action observed, L-asparaginase is widely used in the treatment of Acute Lymphoblastic Leukemia, since these cells use asparagine for their survival. Because it is frequently used as an antineoplastic, it is necessary to evaluate its genotoxic effects. The aim of the present study was to evaluate cellular DNA damage after exposure to L-asparaginase produced by Streptomyces ansochromogenes UFPEDA 3420. NCIH-292, MCF-7 and MOLT-4 neoplastic cell lines and normal PBMC cells were used. L-Asparaginase used in this study was produced by actinobacteria S. ansochromogenes UFPEDA 3420, isolated and purified by chromatographic methods. L-Asparaginase induced micronucleus formation in PBMC cells and tumor lines when compared to the negative control. These data suggest that L-Asp appears to have a genotoxic effect very close to the positive control in normal cells (p < 0.05). The level of genomic damage measured by DNA breaks in alkaline SCGE assay was detected from the lowest concentration (12.5 µg/mL) to the highest concentration (50 µg/mL) for tumor cell lines and PBMC. In view of the above, new genotoxic studies will be carried out to better elucidate L-Asparaginase and its mutagenic potential, still unknown, enough for this drug to be safely used in conventional antineoplastic therapies.


Assuntos
Antineoplásicos/farmacologia , Asparaginase/farmacologia , Dano ao DNA/efeitos dos fármacos , Streptomyces/enzimologia , Streptomyces/metabolismo , Asparaginase/isolamento & purificação , Asparagina/metabolismo , Ácido Aspártico/metabolismo , Linhagem Celular Tumoral/efeitos dos fármacos , Ensaios Enzimáticos , Humanos , Concentração Inibidora 50 , Leucócitos Mononucleares/efeitos dos fármacos , Testes para Micronúcleos
20.
Nat Commun ; 10(1): 693, 2019 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-30741937

RESUMO

ADP-ribosylation is a unique posttranslational modification catalyzed by poly(ADP-ribose) polymerases (PARPs) using NAD+ as ADP-ribose donor. PARPs play an indispensable role in DNA damage repair and small molecule PARP inhibitors have emerged as potent anticancer drugs. However, to date, PARP inhibitor treatment has been restricted to patients with BRCA1/2 mutation-associated breast and ovarian cancer. One of the major challenges to extend the therapeutic potential of PARP inhibitors to other cancer types is the absence of predictive biomarkers. Here, we show that ovarian cancer cells with higher level of NADP+, an NAD+ derivative, are more sensitive to PARP inhibitors. We demonstrate that NADP+ acts as a negative regulator and suppresses ADP-ribosylation both in vitro and in vivo. NADP+ impairs ADP-ribosylation-dependent DNA damage repair and sensitizes tumor cell to chemically synthesized PARP inhibitors. Taken together, our study identifies NADP+ as an endogenous PARP inhibitor that may have implications in cancer treatment.


Assuntos
Antineoplásicos/farmacologia , Dano ao DNA/efeitos dos fármacos , NADP/antagonistas & inibidores , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Poli(ADP-Ribose) Polimerases/efeitos dos fármacos , ADP-Ribosilação , Animais , Biomarcadores , Linhagem Celular Tumoral/efeitos dos fármacos , Reparo do DNA , Proteínas de Grupos de Complementação da Anemia de Fanconi/genética , Feminino , Humanos , Camundongos , NAD/farmacologia , Neoplasias Ovarianas , Fosfotransferases (Aceptor do Grupo Álcool)/efeitos dos fármacos , Poli ADP Ribosilação/efeitos dos fármacos , RNA Helicases/genética
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