RESUMO
The aim of the studies was to evaluate the antiproliferative potential against human tumor cell lines of newly synthetized derivatives containing 4-nitrophenyl group, as well as its impact on developmental toxicity in zebrafish model. We selected 1-(4-nitrobenzoyl)-4-ethylsemicarbazide (APS-1) and 1-[(4-nitrophenyl)acetyl]-4-hexyl-thiosemicarbazide (APS-18) for research. The antiproliferative properties of semicarbazide derivatives were assessed against human cancer cell lines derived from hepatocellular adenocarcinoma (HepG2), renal cell carcinoma (769-P), non-small cell lung cancer (NCI-H1563) and glioblastoma multiforme (LN229) in comparison to the physiological human embryonic kidney (HEK-293) cell line. The influence of the tested substances on the cell cycle and apoptosis was also evaluated. Fish embryo acute toxicity test (FET) was performed based on OECD Guidelines (Test No. 236), and was carried out for the first 5 days post fertilization. The following concentrations of APS-1 and APS-18 were tested: 125-2000 µM and 0.125-1000 µM, respectively. The presented studies on the antiproliferative properties of the new semicarbazide derivatives showed that the compounds APS-1 and APS-18 reduce the viability of human tumor lines. Particularly noteworthy is the strong and selective antiproliferative activity of APS-18 against all neoplastic cell lines, in particular against glioblastoma. Against this tumor line, the compound APS-1 showed an effective inhibitory effect. In the FET we noted that the direct exposure of zebrafish embryos to APS-1 and APS-18 in used range of concentration did not cause morphological abnormalities, including cardiotoxicity. On basis of obtained outcomes it could be concluded that APS-1 and APS-18 may constitute models for further research, design and synthesis of new, safer drugs with more favorable anticancer properties.
Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Animais , Humanos , Peixe-Zebra , Células HEK293 , Antineoplásicos/toxicidade , Proliferação de Células , Linhagem Celular Tumoral , Semicarbazidas/farmacologia , Relação Estrutura-Atividade , Estrutura MolecularRESUMO
Two new (1-2) and three known quinic acid derivatives (3-5) were isolated from the leaves of Schisandra chinensis (Turcz) Baill. The structures of the compounds were determined by spectroscopic methods, especially the NMR techniques, and also by comparison with reported data in the literature. The cytotoxicity activities of these compounds were evaluated on human tumor cell lines LN229 and three of them showed a certain activity.
Assuntos
Lignanas , Schisandra , Lignanas/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Folhas de Planta/química , Ácido Quínico , Schisandra/químicaRESUMO
Melanoma is considered to be one of the most aggressive human tumors. Thus, early molecular diagnosis with risk factor stratification could be an efficacious strategy to increase the survival rates in affected patients. Murine cell lines B16-F1, B16-4A5, and S91 clone M3 are the ones most commonly applied in melanoma research. However, genetic peculiarities of these 3 cell lines have not been studied in detail before. Here, we closed this gap by molecular cytogenetic and array-comparative genomic hybridization studies and the translation of the characterized imbalances into the human genome. This study revealed severely rearranged karyotypes with in parts similar imbalances for all 3 cell lines. Interestingly, they involve genes known to play major roles in human melanoma. These are specifically the oncogenes and tumor suppressor genes, being associated with aggressive forms of melanoma. B16-F1, B16-4A5, and S91 clone M3 revealed aberrations which were similarly observed in human eye and skin but not in human uveal melanoma. Thus, they can be considered as model systems for advanced eye and skin melanoma.
Assuntos
Citogenética , Melanoma/genética , Neoplasias Cutâneas/genética , Animais , Linhagem Celular Tumoral , Hibridização Genômica Comparativa , Olho/metabolismo , Variação Genética , Genoma Humano , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Melanoma Experimental , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Risco , Pele/metabolismo , Neoplasias Uveais/genéticaRESUMO
Targeted nanocarriers could reach new levels of drug delivery, bringing new tools for personalized medicine. It is known that cancer cells overexpress folate receptors on the cell surface compared to healthy cells, which could be used to create new nanocarriers with specific targeting moiety. In addition, magnetic nanoparticles can be guided under the influence of an external magnetic field in different areas of the body, allowing their precise localization. The main purpose of this paper was to decorate the surface of magnetic nanoparticles with poly(2-hydroxyethyl methacrylate) (PHEMA) by surface-initiated atomic transfer radical polymerization (SI-ATRP) followed by covalent bonding of folic acid to side groups of the polymer to create a high specificity magnetic nanocarrier with increased internalization capacity in tumor cells. The biocompatibility of the nanocarriers was demonstrated by testing them on the NHDF cell line and folate-dependent internalization capacity was tested on three tumor cell lines: MCF-7, HeLa and HepG2. It has also been shown that a higher concentration of folic acid covalently bound to the polymer leads to a higher internalization in tumor cells compared to healthy cells. Last but not least, magnetic resonance imaging was used to highlight the magnetic properties of the functionalized nanoparticles obtained.
Assuntos
Ácido Fólico/química , Nanopartículas de Magnetita/química , Poli-Hidroxietil Metacrilato/química , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Células HeLa , Células Hep G2 , Humanos , Células MCF-7 , Tamanho da Partícula , PolimerizaçãoRESUMO
To explore a new set of anticancer agents, a novel series of pyrazolo[4,3-e]pyrido[1,2-a]pyrimidine derivativeshave been designed and synthesized viacyclocondensation reactions of pyrazolo-enaminone with a series of arylidenemalononitriles; compound 5 was obtained from 5-amino-4-cyanopyrazole. The structures of the target compounds were investigated by spectral techniques and elemental analysis (IR, UV-Vis, 1H NMR, 13C NMR and ESI-MS). All compounds were evaluated for their in vitro cytotoxicity employing a panel of different human tumor cell lines, A375, HT29, MCF7, A2780, FaDu as well as non-malignant NIH 3T3 and HEK293 cells. It has been found that the pyrazolo-pyrido-pyrimidine analog bearing a 4-Br-phenyl moiety was the most active toward many cell lines with EC50 values ranging between 9.1 and 13.5 µM. Moreover, in silico docking studies of the latter with six anticancer drug targets, i.e., DHFR, VEGFR2, HER-2/neu, hCA-IX, CDK6 and LOX5, were also performed, in order to gain some insights into their putative mode of binding interaction and to estimate the free binding energy of this bioactive molecule.
Assuntos
Antineoplásicos/farmacologia , Citotoxinas/farmacologia , Pirimidinas/farmacologia , Animais , Linhagem Celular , Linhagem Celular Tumoral , Simulação por Computador , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Células HEK293 , Células HT29 , Humanos , Células MCF-7 , Camundongos , Simulação de Acoplamento Molecular/métodos , Células NIH 3T3 , Pirazóis/farmacologiaRESUMO
Vanadium has a good therapeutic potential, as several biological effects, but few side effects, have been demonstrated. Evidence suggests that vanadium compounds could represent a new class of non-platinum, metal antitumor agents. In the present study, we aimed to characterize the antiproliferative activities of fluorescent vanadyl complexes with acetylacetonate derivates bearing asymmetric substitutions on the ß-dicarbonyl moiety on different cell lines. The effects of fluorescent vanadyl complexes on proliferation and cell cycle modulation in different cell lines were detected by ATP content using the CellTiter-Glo Luminescent Assay and flow cytometry, respectively. Western blotting was performed to assess the modulation of mitogen-activated protein kinases (MAPKs) and relevant proteins. Confocal microscopy revealed that complexes were mainly localized in the cytoplasm, with a diffuse distribution, as in podocyte or a more aggregate conformation, as in the other cell lines. The effects of complexes on cell cycle were studied by cytofluorimetry and Western blot analysis, suggesting that the inhibition of proliferation could be correlated with a block in the G2/M phase of cell cycle and an increase in cdc2 phosphorylation. Complexes modulated mitogen-activated protein kinases (MAPKs) activation in a cell-dependent manner, but MAPK modulation can only partly explain the antiproliferative activity of these complexes. All together our results demonstrate that antiproliferative effects mediated by these compounds are cell type-dependent and involve the cdc2 and MAPKs pathway.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Hidroxibutiratos/química , Pentanonas/química , Compostos de Vanádio/química , Compostos de Vanádio/farmacologia , Transporte Biológico , Proteína Quinase CDC2/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Corantes Fluorescentes , Humanos , Concentração Inibidora 50 , Microscopia Confocal , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosforilação/efeitos dos fármacos , Podócitos/efeitos dos fármacos , Podócitos/ultraestrutura , Inibidores de Proteínas Quinases/farmacologiaRESUMO
Cervical cancer is the fourth most common cancer worldwide in women. Apoptosis reactivation has become the main strategy for decreasing cancer proliferation. There is a need to extend the search for new drugs to implement more effective and less toxic strategies for cervical cancer treatment. Research has been carried out to find new drugs that have minimal side effects and that focus on the tumor microenvironment, particularly in the induction of cellular apoptosis and cell migration and the inhibition of angiogenesis. Potent toxins from snake venoms have shown potential as sources for the synthesis of new drugs with such characteristics. The present work aimed to describe cervical cancer characteristics, associated risk factors, current treatments and to highlight the effects of toxins isolated from the venom of snakes of the Viperidae family on cervical cancer cell lines.
Assuntos
Venenos de Serpentes/farmacologia , Neoplasias do Colo do Útero/tratamento farmacológico , Venenos de Víboras/farmacologia , Animais , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Feminino , Humanos , Neovascularização Patológica , Toxinas Biológicas , Microambiente Tumoral/efeitos dos fármacos , Neoplasias do Colo do Útero/metabolismoRESUMO
Although two- and three-dimensional in vitro studies of breast tumor cell lines have increased our knowledge on tumor growth and metastasis formation, the complex in vivo microenvironment is not taken into consideration. The goal of our study was to illustrate the in vivo morphology and motility of widely used breast tumor cell lines. Intravital microscopy allows real-time visualization of individual cells inside tissues of living animals. We used this technique to study breast cancer migration in the complex orthotopic microenvironment. More specifically, we characterized cell morphology, cell-cell interactions, polarity and motility of mouse tumor cell lines 4T1 and mILC-1 and human tumor cell lines MDA-MB-231 and T47D. Almost all measured parameters were remarkably heterogeneous even between positions within the same tumor. Migrating tumor cells were circular in all tumor models, indicating predominantly amoeboid motility. This overview of the in vivo characteristics of mouse and human breast tumor cell lines illustrates their heterogeneity and complexity in real life, and additionally exemplifies caution should be taken to extrapolate in vitro assays of tumor invasiveness.
Assuntos
Neoplasias da Mama , Linhagem Celular Tumoral , Animais , Neoplasias da Mama/patologia , Comunicação Celular , Movimento Celular , Polaridade Celular , Feminino , Heterogeneidade Genética , Humanos , Microscopia Intravital , Camundongos , Camundongos Endogâmicos BALB C , Transplante de NeoplasiasRESUMO
The colchicine site inhibitors (CSIs) displayed both antimitotic and vascular disrupting activities, therefore are promising potential antitumor agents. In this study, a series 1-phenyl-4,5-dihydro-2H-benzo[e]indazoles were found as new CSIs of which the bioactive configuration was locked. Among them, compounds C1 and C2 displayed the best activity, with tubulin polymerization IC50 of 3.4 and 1.5⯵M, and growth IC50 of low nanomolar concentrations against human colon cancer cell lines. In addition, compound C1 showed excellent broad-spectrum antitumor activity in the NCI-60 Human Tumor Cell Lines Screen, encouraging further study of this antitumor compound.
Assuntos
Antineoplásicos/farmacologia , Colchicina/antagonistas & inibidores , Neoplasias do Colo/tratamento farmacológico , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Colchicina/metabolismo , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Polimerização/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Starting from the pioneering discovery of picoplatin and phenanthriplatin, many efforts were realized by different research groups in the synthesis of different platinum(II) complexes, bearing a N-heterocycle moiety active as anticancer agents in different types of solid tumors. This review deals in particular with both the bifunctional and monofunctional platinum drugs, not only in dichloride platinum(II) complexes, but also in recent advances in modern platinum structures, i.e. cationic ones. Both the in vitro and in vivo studies of these anticancer agents are taken into account, with a special consideration for aggressive and orphan in treatment tumors.
Assuntos
Antineoplásicos/farmacologia , Compostos Heterocíclicos/farmacologia , Neoplasias/tratamento farmacológico , Compostos Organoplatínicos/farmacologia , Animais , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Compostos Heterocíclicos/química , Humanos , Estrutura Molecular , Neoplasias/patologia , Compostos Organoplatínicos/química , Relação Estrutura-AtividadeRESUMO
Novel neolymphostin-based antibody-drug conjugate (ADC) precursors were synthesized either through amide couplings between both cleavable and non-cleavable linkers and neolymphostin derivatives, or through Cu(I)-catalyzed acetylene-azide click cycloadditon between non-cleavable linkers and neolymphostin acetal derivatives. These precursors were site-specifically conjugated to cysteine mutant trastuzumab-A114C to provide neolymphostin-based ADCs. Preliminary in vitro data indicated that the corresponding ADCs were active against HER2-expressing tumor cell lines, thus providing a proof-of-concept for using neolymphostin as ADC-based anticancer agents.
Assuntos
Aminoquinolinas/farmacologia , Antineoplásicos/farmacologia , Imunoconjugados/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Pirróis/farmacologia , Trastuzumab/farmacologia , Aminoquinolinas/síntese química , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Mutação , Inibidores de Fosfoinositídeo-3 Quinase/síntese química , Estudo de Prova de Conceito , Pirróis/síntese química , Trastuzumab/genéticaRESUMO
Several marine natural linear prenylquinones/hydroquinones have been identified as anticancer and antimutagenic agents. Structure-activity relationship studies on natural compounds and their synthetic analogs demonstrated that these effects depend on the length of the prenyl side chain and on the type and position of the substituent groups in the quinone moiety. Aiming to broaden the knowledge of the underlying mechanism of the antiproliferative effect of these prenylated compounds, herein we report the synthesis of two quinones 4 and 5 and of their corresponding dioxothiazine fused quinones 6 and 7 inspired to the marine natural product aplidinone A (1), a geranylquinone featuring the 1,1-dioxo-1,4-thiazine ring isolated from the ascidian Aplidium conicum. The potential effects on viability and proliferation in three different human cancer cell lines, breast adenocarcinoma (MCF-7), pancreas adenocarcinoma (Bx-PC3) and bone osteosarcoma (MG-63), were investigated. The methoxylated geranylquinone 5 exerted the highest antiproliferative effect exhibiting a comparable toxicity in all three cell lines analyzed. Interestingly, a deeper investigation has highlighted a cytostatic effect of quinone 5 referable to a G0/G1 cell-cycle arrest in BxPC-3 cells after 24 h treatment.
Assuntos
Antineoplásicos/farmacologia , Produtos Biológicos/farmacologia , Terpenos/farmacologia , Adenocarcinoma/tratamento farmacológico , Antineoplásicos/síntese química , Antineoplásicos/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Neoplasias Ósseas/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Células MCF-7 , Osteossarcoma/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Relação Estrutura-Atividade , Terpenos/síntese química , Terpenos/químicaRESUMO
Caribbean sponges of the genus Smenospongia are a prolific source of chlorinated secondary metabolites. The use of molecular networking as a powerful dereplication tool revealed in the metabolome of S. aurea two new members of the smenamide family, namely smenamide F (1) and G (2). The structure of smenamide F (1) and G (2) was determined by spectroscopic analysis (NMR, MS, ECD). The relative and the absolute configuration at C-13, C-15, and C-16 was determined on the basis of the conformational rigidity of a 1,3-disubstituted alkyl chain system (i.e., the C-12/C-18 segment of compound (1). Smenamide F (1) and G (2) were shown to exert a selective moderate antiproliferative activity against cancer cell lines MCF-7 and MDA-MB-231, while being inactive against MG-63.
Assuntos
Produtos Biológicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Poríferos/química , Animais , Antineoplásicos/farmacologia , Região do Caribe , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Fibroblastos , Humanos , Células MCF-7 , Espectroscopia de Ressonância Magnética , Metaboloma , Estrutura Molecular , Poríferos/metabolismoRESUMO
A new fluorometric method is delineated for the detection of RNase H activity by combining DNAzyme with reduced graphene oxide (rGO). In the absence of RNase H, the fluorescence of FAM-labeled probe is quenched due to the strong adsorption on the rGO. The presence of RNase H can release the active DNAzyme from the DNA-RNA chimeric strand. This triggers the cleavage of the signal probe at the rA site with the help of the cofactor Mg2+. The recycle cleavage can directly result in the amplified signal emitted by the FAM-labeled short fragment. The method allows the activity of RNase H to be detected in a linear range of 0.01 to 5 U·mL-1. The detection limit of 0.018 U·mL-1 is calculated by the principle of three-time standard deviation over the blank signal. Then, RNase H-targeting natural compounds were screened for their inhibitory action. Among the investigated compounds, five were screened as RNase H inhibitors in a concentration-dependent manner, and 4 compounds were identified as activators. Finally, the method was reliably used for discriminating the difference of RNase H activity in human serum. It is found that RNase H activity was upregulated in patients with hepatitis C virus infection. Graphical abstract The schematic presentation of rGO-DNAzyme-based RNase H detection. RNase H triggers the active DNAzyme releasing from the DNA-RNA chimeric strand, which can cleavage probes to FAM-labeled short fragments and make the fluorescence signal cycle amplified.
Assuntos
Sondas de DNA/química , DNA Catalítico/química , Grafite/química , Ribonuclease H/sangue , Espectrometria de Fluorescência/métodos , Linhagem Celular Tumoral , Inibidores Enzimáticos/química , Fluoresceínas/química , Corantes Fluorescentes/química , Humanos , Limite de Detecção , Ribonuclease H/antagonistas & inibidoresRESUMO
Following our previous work on the antitumor activity of acetylated flavonosides, a new acetylated xanthonoside, 3,6-bis(2,3,4,6-tetra-O-acetyl-ß-glucopyranosyl)xanthone (2), was synthesized and discovered as a potent inhibitor of tumor cell growth. The synthesis involved the glycosylation of 3,6-di-hydroxyxanthone (1) with acetobromo-α-d-glucose. Glycosylation with silver carbonate decreased the amount of glucose donor needed, comparative to the biphasic glycosylation. Xanthone 2 showed a potent anti-growth activity, with GI50 < 1 µM, in human cell lines of breast, lung, and glioblastoma cancers. Current treatment for invasive brain glioma is still inadequate and new agents against glioblastoma with high brain permeability are urgently needed. To overcome these issues, xanthone 2 was encapsulated in a liposome. To increase the well-known low stability of these drug carriers, a proliposome formulation was developed using the spray drying method. Both formulations were characterized and compared regarding three months stability and in vitro anti-growth activity. While the proliposome formulation showed significantly higher stability, it was at the expense of losing its biocompatibility as a drug carrier in higher concentrations. More importantly, the new xanthone 2 was still able to inhibit the growth of glioblastoma cells after liposome formulation.
Assuntos
Proliferação de Células/efeitos dos fármacos , Glioma/tratamento farmacológico , Lipossomos/farmacologia , Xantonas/farmacologia , Carbonatos/química , Linhagem Celular Tumoral , Portadores de Fármacos/síntese química , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Glioma/patologia , Glucose/química , Glicosilação/efeitos dos fármacos , Humanos , Lipossomos/síntese química , Lipossomos/química , Compostos de Prata/química , Xantonas/síntese química , Xantonas/químicaRESUMO
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 MicronúcleosRESUMO
The sonic Hedgehog/GLI signaling pathway (HH) is critical for maintaining tissue polarity in development and contributes to tumor stemness. Transcription factors GLI1â»3 are the downstream effectors of HH and activate oncogenic targets. To explore the completeness of the expression of HH components in tumor cells, we performed a screen for all HH proteins in a wide spectrum of 56 tumor cell lines of various origin using Western blot analysis. Generally, all HH proteins were expressed. Important factors GLI1 and GLI2 were always expressed, only exceptionally one of them was lowered, suggesting the functionality of HH in all tumors tested. We determined the effect of a GLI inhibitor GANT61 on proliferation in 16 chosen cell lines. More than half of tumor cells were sensitive to GANT61 to various extents. GANT61 killed the sensitive cells through apoptosis. The inhibition of reporter activity containing 12xGLI consensus sites by GANT61 and cyclopamine roughly correlated with cell proliferation influenced by GANT61. Our results recognize the sensitivity of tumor cell types to GANT61 in cell culture and support a critical role for GLI factors in tumor progression through restraining apoptosis. The use of GANT61 in combined targeted therapy of sensitive tumors, such as melanomas, seems to be immensely helpful.
Assuntos
Proteínas Hedgehog/metabolismo , Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Piridinas/farmacologia , Pirimidinas/farmacologia , Proteína GLI1 em Dedos de Zinco/metabolismo , Proteína Gli2 com Dedos de Zinco/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HeLa , Humanos , Células Jurkat , Neoplasias/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacosRESUMO
New derivatives of phaeosphaeride A (PPA) were synthesized and characterized. Anti-tumor activity studies were carried out on the HCT-116, PC3, MCF-7, A549, Ð562, NCI-Ð929, Jurkat, THP-1, RPMI8228 tumor cell lines, and on the HEF cell line. All of the compounds synthesized were found to have better efficacy than PPA towards the tumor cell lines mentioned. Compound 6 was potent against six cancer cell lines, HCT-116, PC-3, K562, NCI-H929, Jurkat, and RPMI8226, showing a 47, 13.5, 16, 4, 1.5, and 7-fold increase in anticancer activity comparative to those of etoposide, respectively. Compound 1 possessed selectivity toward the NCI-H929 cell line (IC50 = 1.35 ± 0.69 µM), while product 7 was selective against three cancer cell lines, HCT-116, MCF-7, and NCI-H929, each having IC50 values of 1.65 µM, 1.80 µM and 2.00 µM, respectively.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Células A549 , Antineoplásicos/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Humanos , Células Jurkat , Células MCF-7 , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
In the clinic some anti-tumor drugs have shown damage to normal blood vessels, which could lead to vascular diseases. Therefore, it is necessary to evaluate the effects of anti-tumor drugs on normal blood vessels at the beginning of the drug design process. In this study, ligustrazine (TMP) and flavonoids were selected as raw materials. Sixteen novel TMP-flavonoid derivatives were designed and synthesized. Interestingly, compounds 14 and 16 were obtained by hydrolysis of a dihydroflavone to a chalcone under alkaline conditions. The cytotoxicity of the TMP-flavonoid derivatives was evaluated on five human tumor cell lines and one classical type of normal endothelial cell lines (HUVEC-12) by an MTT assay. Part of the derivatives showed better anti-tumor activities than the corresponding raw materials. Among them, compound 14 exhibited the closest activity to the positive control against the Bel-7402 cell line (IC50 = 10.74 ± 1.12 µM; DDP IC50 = 6.73 ± 0.37 µM) and had no toxicity on HUVEC-12 (IC50 > 40 µM). Subsequently, fluorescence staining and flow cytometry analysis indicated that compound 14 could induce apoptosis of Bel-7402 cell lines. Moreover, the structure-activity relationships of these derivatives were briefly discussed.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Desenho de Fármacos , Flavonoides/química , Flavonoides/farmacologia , Pirazinas/química , Pirazinas/farmacologia , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Sintética , Flavonoides/síntese química , Células Endoteliais da Veia Umbilical Humana , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Pirazinas/síntese química , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Cellular based therapeutic approaches for cancer rely on careful consideration of finding the optimal cell to execute the cellular goal of cancer treatment. Cell lines and primary cell cultures have been used in some studies to compare the in vitro and in vivo efficacy of autologous vs allogeneic tumour cell vaccines. METHODS: This study examines the effect of γ-irradiation on a range of tumor cell lines in conjunction with suicide gene therapy of cancer. To determine the efficacy of this modality, a series of in vitro and in vivo experiments were conducted using genetically modified and unmodified tumor cell lines. RESULTS: Following co-culture of HSV-TK modified tumor cells and unmodified tumor cells both in vitro and in vivo we observed that the PA-STK ovarian tumor cells were sensitive to γ-irradiation, completely abolishing their ability to induce bystander killing of unmodified tumor cells. In contrast, TK-modified human and mouse mesothelioma cells were found to retain their in vitro and in vivo bystander killing effect after γ-irradiation. Morphological evidence was consistent with the death of PA-STK cells being by pyknosis after γ-irradiation. These results suggest that PA-STK cells are not suitable for clinical application of suicide gene therapy of cancer, as lethal γ-irradiation (100 Gy) interferes with their bystander killing activity. However, the human mesothelioma cell line CRL-5830-TK retained its bystander killing potential after exposure to similarly lethal γ-irradiation (100 Gy). CRL-5830 may therefore be a suitable vehicle for HSV-TK suicide gene therapy. CONCLUSIONS: This study highlights the diversity among tumor cell lines and the careful considerations needed to find the optimal tumor cell line for this type of suicide gene therapy of cancer.