Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 199
Filtrar
1.
Apoptosis ; 2021 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-34837562

RESUMO

Reigning of the abnormal gene activation associated with survival signalling in lung cancer leads to the anomalous growth and therapeutic failure. Targeting specific cell survival signalling like JAK2/STAT3 nexus has become a major focus of investigation to establish a target specific treatment. The 2-bromobenzoyl-4-methylphenoxy-acetyl hydra acetyl Coumarin (BP-1C), is new anti-neoplastic agent with apoptosis inducing capacity. The current study was aimed to develop antitumor phramacophore, BP-1C as JAK2 specific inhibitor against lung neoplastic progression. The study validates and identifies the molecular targets of BP-1C induced cell death. Cell based screening against multiple cancer cell lines identified, lung adenocarcinoma as its specific target through promotion of apoptosis. The BP-1C is able to induce, specific hall marks of apoptosis and there by conferring anti-neoplastic activity. Validation of its molecular mechanism, identified, BP-1C specifically targets JAK2Tyr1007/1008 phosphorylation, and inhibits its downstream STAT3Tyr705 signalling pathway to induce cell death. As a consequence, modulation in Akt/Src survival signal and altered expression of interwoven apoptotic genes were evident. The results were reproducible in an in-vivo LLC tumor model and in-ovo xenograft studies. The computational approaches viz, drug finger printing confers, BP-1C as novel class JAK2 inhibitor and molecular simulations studies assures its efficiency in binding with JAK2. Overall, BP-1C is a novel JAK2 inhibitor with experimental evidence and could be effectively developed into a promising drug for lung cancer treatment.

2.
Pharmacol Rep ; 73(5): 1344-1360, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34109572

RESUMO

BACKGROUND: Imbalance and instability in the structure of the DNA have become major characteristics of cancer. In response to DNA damage, DNA damage response (DDR) protein, ataxia telangiectasia mutated (ATM), plays a pivotal role in the modulation of regulatory regions responsible for inhibition of apoptosis, thereby neoplastic progression. METHODS: A new series of DPA (7a-t) were synthesized, characterized. Anti-proliferative studies to identify the lead compound were carried out by LDH and MTT assay. Apoptosis/DNA damage was measured through FACS, Annexin-v staining, TUNEL and Comet assay. Elucidation of molecular mechanism through immunoblot and further validation of the drug effect through in vivo approaches. RESULTS: Initial in vitro anti-proliferative screening of Compounds DPA (7a-t) against multiple cancer cell lines identified Compound DPA (7n) as a potent cytotoxic molecule with IC50 value of 4.3 µM. Down the line, in vitro and in vivo evaluation of Compound DPA (7n) inferred that it has apoptotic inducing potentiality. Further, evaluation of molecular mechanism inferred that Compound DPA (7n) effectively modulates ATM phosphorylation only, eventually altering downstream signalling pathways. CONCLUSIONS: Compound DPA (7n) emerged as a potent proapoptotic and anti-neoplastic agent by inhibiting ATM kinase activity both in vitro and in vivo. The conferring results ascertain that the drug could be developed as a new ATM kinase inhibitor with anti-cancer capacity.

3.
J Contemp Dent Pract ; 21(2): 190-196, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32381826

RESUMO

AIM: The aim of the study was to evaluate the dimensional accuracy of three combinations of polyvinyl siloxane impression material by double-mix single-step impression technique. MATERIALS AND METHODS: Metal master model was made according to the ADA specification no. 19; ISO 4823:2000/AMD 2007. Impressions were made using perforated custom-made metallic trays of 2 mm and 4 mm spacing, the impression materials used were putty, heavy body, regular body and light body. A total of 30 impressions were made by single-step technique and poured in die stone to obtain resultant cast. Ten impressions were made of each combination of polyvinyl siloxane (PVS). Three dimensions (interabutment distance, height and diameter) on resultant cast were measured and compared with metal master model. The results were statistically analyzed and tabulated. RESULTS: Diameter of abutment, the height of abutment and interabutment distance in each group were larger in dimensions as compared with metal master model. The dimensional discrepancies of group I, group II and group III casts when compared with the master model were significantly different from each other. The least difference was found in group I. CONCLUSION: The one-step putty-light body combination (group I) produced the most accurate stone casts compared with one-step heavy body-light body and regular body-light body combinations. CLINICAL SIGNIFICANCE: In everyday dental practice, impression making is imperative. Hence, by doing this study, we tried to find out which material combination is suitable to give us predictable and accurate results.


Assuntos
Técnica de Moldagem Odontológica , Modelos Dentários , Polivinil , Siloxanas
4.
Biomed Pharmacother ; 112: 108707, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30970513

RESUMO

The synthesis and antiproliferative effect of a series of quinoline and thiazole containing coumarin analogs 12a-d and 13a-f respectively, on mice leukemic cells was performed. The chemical structures of newly synthesized compounds were confirmed by IR, 1H NMR, 13C NMR and mass spectral analysis. The result indicates that, 7-methoxy-2-oxo-2H-chromene-3-carboxylic acid [4-(4-methoxy-phenyl)-thiazol-2-yl]-amide (13f) showed potent activity against EAC and DLA cells in MTT (15.3 µM), tryphan blue (15.6 µM) and LDH (14.2 µM) leak assay with 5-fluorouracil as a standard. Further, the anti-neoplastic effect of the compound 13f was verified against Ehrlich ascites tumour by BrdU incorporation, TUNEL, FACS and DNA fragmentation assays. Experimental data showed that compound 13f induces the apoptotic cell death by activating apoptotic factors such as caspase-8 &-3, CAD, Cleaved PARP, γ-H2AX and by degrading genomic DNA of cancer cells and thereby decreasing the ascitic tumour development in mice. Besides, compound 13f was also subjected for docking studies to approve the in vitro and in vivo studies. The data revealed that the compound 13f has very good interaction with caspase 3 protein by binding with amino acid Arg 207 through hydrogen bond.


Assuntos
Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Carcinoma de Ehrlich/tratamento farmacológico , Cumarínicos/síntese química , Quinolinas/química , Tiazóis/química , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Antineoplásicos/toxicidade , Carcinoma de Ehrlich/patologia , Linhagem Celular Tumoral , Simulação por Computador , Cumarínicos/química , Cumarínicos/uso terapêutico , Cumarínicos/toxicidade , Dose Letal Mediana , Camundongos , Relação Estrutura-Atividade
5.
Biomed Pharmacother ; 103: 1446-1455, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29864929

RESUMO

Ten new 2(4-hydroxy-3-benzoyl) benzamide-5-phenyl-1,3,4-oxadiazole derivatives (10a-j) were synthesized by coupling 3-benzoyl-4-hydroxybenzoic acid (5) with 2-amino-5-phenyl-1,3,4-oxadiazoles (9a-j). The structures of these compounds were confirmed by IR, 1H, 13C NMR, and mass spectra, and also by elemental analyses. The anti-inflammatory activity of the compounds 10a-j were investigated by screening them against human red blood cells (HRBC) in-vitro. The results reveal that among this series, compound 10j with hydroxy substituent, particularly at the ortho position of the phenyl ring attached to the 5th carbon atom of the oxadiazole ring possess significant membrane stabilizing activity in comparison with the control. Further, in-vivo chick chorioallantoic membrane (CAM) and rat corneal anti-angiogenesis assays were performed to assess the effect of compound 10j on endothelial cell migration. This confirmed that compound 10j inhibits the proliferation of endothelial cells. Anti-inflammatory studies detected the amelioration of carrageen induced rat hind paw edema. Further in-vivo and in-silico approaches revealed the inhibition of inflammatory marker enzyme cyclooxygenase-2 (Cox-2) and myleoperoxidase (MPO). The study reports that the compound 10j effectively act against the inflammatory mediated anti-angiogenic disorders which could be translated into a new drug in future.


Assuntos
Benzofenonas/síntese química , Benzofenonas/uso terapêutico , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Ciclo-Oxigenase 2/metabolismo , Edema/tratamento farmacológico , Inflamação/tratamento farmacológico , Oxidiazóis/síntese química , Oxidiazóis/uso terapêutico , Animais , Benzofenonas/química , Benzofenonas/farmacologia , Galinhas , Inibidores de Ciclo-Oxigenase 2/farmacologia , Edema/complicações , Edema/enzimologia , Humanos , Inflamação/complicações , Inflamação/enzimologia , Masculino , Neovascularização Fisiológica/efeitos dos fármacos , Oxidiazóis/química , Oxidiazóis/farmacologia , Ratos
6.
Life Sci ; 199: 139-150, 2018 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-29524520

RESUMO

Aim Deformity in the cellular homeostatic event associated with cell survival and apoptosis are committing factors for carcinogenesis. Interventions of these events by pharmacologically active agent gain predominance in cancer treatment. In current investigation Solanidine, a steroidal alkaloid was evaluated on tumorigenesis by targeting death signal using multiple tumor cells and model systems. MAIN METHODS: Anti-proliferative effect was evaluated using cytotoxic studies. Prolonged cytotoxic effect of Solanidine was examined by colony formation assay. Exhibition of apoptotic hallmark induced by Solanidine was examined using FACS analysis, Annexin-V staining, Acridine orange staining, TUNEL assay. Altered gene expression was evaluated using Immunoblot, Immunofluorescence and Immunohistochemistry technique. In-vitro results were revalidated in EAC solid tumor and CAM xenograft model. KEY FINDINGS: Solanidine exerts its potential effect in a target specific manner. The cytotoxic/anticlonogenic activity was due to induction of typical cellular apoptotic hallmarks and cell cycle blockage at S-G2/M phase. The molecular events underlying this effect is through activation of intrinsic pathway via Bax, Bad and Cytochrome c activation by neutralizing Bcl-2 expression, along with downregulated PI3K/Akt survival signal. As a consequence, downstream pro apoptogenic gene, active Caspase-3 was over expressed by Solanidine to cleave its substrate PARP and promotes nuclear import of DFF-40. Anti-carcinogenic aptitude was further confirmed by murine solid tumors and in-vivo CAM xenograft studies. SIGNIFICANCE: Solanidine emerged as active molecule against tomorigenesis by activating nuclear import of DFF-40 mediated nucleosomal disruption and cell demise. It can be developed as a potential apoptogenic small molecule for cancer therapy.


Assuntos
Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Alcaloides/farmacologia , Morte Celular/efeitos dos fármacos , Desoxirribonucleases/metabolismo , Diosgenina/farmacologia , Nucleossomos/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Células A549 , Transporte Ativo do Núcleo Celular/fisiologia , Alcaloides/uso terapêutico , Animais , Morte Celular/fisiologia , Diosgenina/uso terapêutico , Relação Dose-Resposta a Droga , Células HEK293 , Células Hep G2 , Humanos , Células MCF-7 , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
7.
Eur J Med Chem ; 143: 1826-1839, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29133037

RESUMO

Tumor microenvironment is a complex multistep event which involves several hallmarks that transform the normal cell into cancerous cell. Designing the novel antagonistic molecule to reverse the tumor microenvironment with specific target is essential in modern biological studies. The novel 4-phenyl-2-phenoxyacetamide thiazole analogues 8a-ab were synthesized in multistep process, then screened and assessed for cytotoxic and anti-proliferative effects in vitro against multiple cancer cells of different origin such as MCF-7, A549, EAC and DLA cells which revealed that compound 8f with fluoro and methyl substitute has potential cytotoxic efficacy with an average IC50 value of ˜ 13 µM. The mechanism of cytotoxicity assessed for anti-tumor studies both in ascites and solid tumor models in-vivo inferred the regressed tumor activity. This is due to changes in the cause of tumor microenvironment with crackdown of neovascularization and evoking apoptosis process as assessed by CAM, corneal vascularization and apoptotic hallmarks in 8f treated cells. The molecular gene studies inferred involvement of HIF-1upregulation and stabilization of p53 which are interlinked in signaling as conferred by immunoblot analysis.


Assuntos
Acetamidas/farmacologia , Antineoplásicos/farmacologia , Neovascularização Patológica/tratamento farmacológico , Tiazóis/farmacologia , Hipóxia Tumoral/efeitos dos fármacos , Acetamidas/síntese química , Acetamidas/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Neovascularização Patológica/patologia , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química , Células Tumorais Cultivadas
8.
Biomed Pharmacother ; 95: 419-428, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28863382

RESUMO

Disrupted redox balance is implicated in multiple pathologies including malignant progression and tumor angiogenesis. In this investigation, we report the design and development of novel and effective ROS detoxifying azo-hydrazone molecules targeting malignant pathologies and neoangiogenesis. A series of azo-derivatives conjugated to hydrazones moieties (9a-j) were synthesized using Nano BF3·SiO2. The compounds (9a-j) were screened for in-vitro antioxidant and lipid peroxidation inhibitory activity. Among the series 9a-j, compound 9f potently quenched biologically relevant radicals such as superoxide and hydrogen peroxide which emerged as the lead ROS detoxifying molecules. Compound 9f potently inhibited the proliferative capability of Daltons Lymphoma Ascites (DLA) tumor cells in-vivo in dose dependent manner. Regressed tumor progression was correlated with pronounced endogenous antioxidant enzyme superoxide dismutase and catalase in-vivo. Also, ROS levels were severely suppressed in 9f treated mice as assessed by lapsed lipid peroxidation. Altered enzymic and ROS levels in-vivo by 9f were implicated in suppressed VEGF secretion leading to regressed tumor neovasculature and tumor growth. Considering together, it is evident that the synthetic azo-hydrazone analogue 9f with potent ROS scavenging efficacy inhibits tumor progression and neo-angiogenesis.


Assuntos
Boranos/química , Carcinogênese/efeitos dos fármacos , Homeostase , Hidrazonas/síntese química , Hidrazonas/uso terapêutico , Neovascularização Patológica/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Dióxido de Silício/química , Animais , Antioxidantes/metabolismo , Ascite/patologia , Progressão da Doença , Desenho de Fármacos , Hidrazonas/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Camundongos , Neovascularização Patológica/sangue , Relação Estrutura-Atividade , Fator A de Crescimento do Endotélio Vascular/metabolismo
9.
J Neuroinflammation ; 14(1): 117, 2017 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-28599652

RESUMO

Multiple sclerosis (MS) is a chronic debilitating disease of the central nervous system primarily mediated by T lymphocytes with specificity to neuronal antigens in genetically susceptible individuals. On the other hand, myasthenia gravis (MG) primarily involves destruction of the neuromuscular junction by antibodies specific to the acetylcholine receptor. Both autoimmune diseases are thought to result from loss of self-tolerance, which allows for the development and function of autoreactive lymphocytes. Although the mechanisms underlying compromised self-tolerance in these and other autoimmune diseases have not been fully elucidated, one possibility is numerical, functional, and/or migratory deficits in T regulatory cells (Tregs). Tregs are thought to play a critical role in the maintenance of peripheral immune tolerance. It is believed that Tregs function by suppressing the effector CD4+ T cell subsets that mediate autoimmune responses. Dysregulation of suppressive and migratory markers on Tregs have been linked to the pathogenesis of both MS and MG. For example, genetic abnormalities have been found in Treg suppressive markers CTLA-4 and CD25, while others have shown a decreased expression of FoxP3 and IL-10. Furthermore, elevated levels of pro-inflammatory cytokines such as IL-6, IL-17, and IFN-γ secreted by T effectors have been noted in MS and MG patients. This review provides several strategies of treatment which have been shown to be effective or are proposed as potential therapies to restore the function of various Treg subsets including Tr1, iTr35, nTregs, and iTregs. Strategies focusing on enhancing the Treg function find importance in cytokines TGF-ß, IDO, interleukins 10, 27, and 35, and ligands Jagged-1 and OX40L. Likewise, strategies which affect Treg migration involve chemokines CCL17 and CXCL11. In pre-clinical animal models of experimental autoimmune encephalomyelitis (EAE) and experimental autoimmune myasthenia gravis (EAMG), several strategies have been shown to ameliorate the disease and thus appear promising for treating patients with MS or MG.


Assuntos
Esclerose Múltipla/imunologia , Esclerose Múltipla/terapia , Miastenia Gravis Autoimune Experimental/imunologia , Miastenia Gravis Autoimune Experimental/terapia , Linfócitos T Reguladores/imunologia , Animais , Humanos , Tolerância Imunológica/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Imunoterapia/métodos , Imunoterapia/tendências , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Esclerose Múltipla/metabolismo , Miastenia Gravis Autoimune Experimental/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/metabolismo
10.
Clin Exp Immunol ; 189(1): 21-35, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28268243

RESUMO

Neovascularization and jeopardized immunity has been critically emphasized for the establishment of malignant progression. Lectins are the diverse class of carbohydrate interacting proteins, having great potential as immunopotentiating and anti-cancer agents. The present investigation sought to demonstrate the anti-proliferative activity of Dolichos lablab lectin (DLL) encompassing immunomodulatory attributes. DLL specific to glucose and mannose carbohydrate moieties has been purified to homogeneity from the common dietary legume D. lablab. Results elucidated that DLL agglutinated blood cells non-specifically and displayed striking mitogenicity to human and murine lymphocytes in vitro with interleukin (IL)-2 production. The DLL-conditioned medium exerted cytotoxicity towards malignant cells and neoangiogenesis in vitro. Similarly, in-vivo anti-tumour investigation of DLL elucidated the regressed proliferation of ascitic and solid tumour cells, which was paralleled with blockade of tumour neovasculature. DLL-treated mice showed an up-regulated immunoregulatory cytokine IL-2 in contrast to severely declined levels in control mice. Mechanistic validation revealed that DLL has abrogated the microvessel formation by weakening the proangiogenic signals, specifically nuclear factor kappa B (NF-κB), hypoxia inducible factor 1α (HIF-1 α), matrix metalloproteinase (MMP)-2 and 9 and vascular endothelial growth factor (VEGF) in malignant cells leading to tumour regression. In summary, it is evident that the dietary lectin DLL potentially dampens the malignant establishment by mitigating neoangiogenesis and immune shutdown. For the first time, to our knowledge, this study illustrates the critical role of DLL as an immunostimulatory and anti-angiogenic molecule in cancer therapeutics.


Assuntos
Mitógenos/farmacologia , Neoplasias/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Lectinas de Plantas/administração & dosagem , Lectinas de Plantas/farmacologia , Células A549 , Aglutinação , Animais , Aorta/efeitos dos fármacos , Técnicas de Cultura de Células , Membrana Corioalantoide/efeitos dos fármacos , Córnea/irrigação sanguínea , Córnea/efeitos dos fármacos , Dissacarídeos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Imunomodulação , Interleucina-2/metabolismo , Metaloproteinase 3 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Mitógenos/imunologia , Lectinas de Plantas/imunologia , Ratos , Ratos Wistar , Sementes/química , Fator A de Crescimento do Endotélio Vascular/metabolismo
11.
Bioorg Chem ; 71: 55-66, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28139247

RESUMO

A series of novel 4-benzyl-morpholine-2-carboxylic acid N'-[2-(4-benzoyl-phenoxy)-acetyl]-hydrazide derivatives 8a-j has been synthesized from (4-hydroxy-aryl)-aryl methanones through a multi-step reaction sequence and then evaluated for anti-proliferative activity in vitro against various types of neoplastic cells of mouse and human such as DLA, EAC, MCF-7 and A549 cells. From the cytotoxic studies and structural activity relationship of compounds 8a-j, it is clear that methyl group on the B ring of benzophenone is essential for antiproliferative activity and bromo at ortho position (compound 8b) and methyl at para position (compound 8f) on A ring of benzophenone are significant for extensive anti-mitogenic activity. Investigation on clonogenesis and Fluorescence-activated cell sorting suggests that compounds 8b and 8f have the potency to exhibit the prolonged activity with cell cycle arrest on G2/M phase against cancer progression. Further, the compounds 8b and 8f inhibit murine ascites lymphoma through caspase activated DNase mediated apoptosis.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Benzofenonas/química , Benzofenonas/farmacologia , Morfolinas/química , Morfolinas/farmacologia , Animais , Antineoplásicos/síntese química , Benzofenonas/síntese química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Camundongos , Morfolinas/síntese química , Neoplasias/tratamento farmacológico , Relação Estrutura-Atividade
12.
Biochem Biophys Res Commun ; 484(1): 85-92, 2017 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-28104392

RESUMO

Neoplastic cells often reside in distinctive tumor hypoxia armed with a series of adaptive responses including oxidative stress, defective apoptotic machinery and neoangiogenesis, through that further confer cell survival improvement. Plants still acts as reservoir of natural chemicals to provide newer active pharmacophores. Scutellarein is flavones which has wide range of pharmacophoral effects. In our current research, scutellarein employed for targeting oxidative stress mediated tumor angiogenesis and apoptotic nuclear fragmentation. Experimental results revealed that scutellarein has antiproliferative index against multiple cancer cell lines and diminished the oxidative stress and tumor development of murine ascitic lymphoma & inflammatory hepatocellular carcinoma. Eventual consequences lead to reduced neovessel formation by abrogating angiogeneic factors cytokine-VEGF-A, Flt-1, HIF-1α, MMP-2 and MMP-9 and reversing of evading apoptosis by activating caspase-3 activated DNA fragmentation factor (DFF-40) mediated nucleosomal degradation. In summary, our experimental evidences suggest that scutellarein has strong potentiality to attenuate the tumor development by modulating sprouting neovasculature and DFF-40 mediated apoptosis.


Assuntos
Apigenina/farmacologia , Carcinogênese/efeitos dos fármacos , Desoxirribonucleases/farmacologia , Neovascularização Patológica/induzido quimicamente , Nucleossomos/metabolismo , Fator A de Crescimento do Endotélio Vascular/fisiologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Ratos
13.
Biochem Pharmacol ; 125: 26-40, 2017 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-27838496

RESUMO

Hypoxia is an important module in all solid tumours to promote angiogenesis, invasion and metastasis. Stabilization and subsequent nuclear localization of HIF-1α subunits result in the activation of tumour promoting target genes such as VEGF, MMPs, Flt-1, Ang-1 etc. which plays a pivotal role in adaptation of tumour cells to hypoxia. Increased HIF-α and its nuclear translocation have been correlated with pronounced angiogenesis, aggressive tumour growth and poor patient prognosis leading to current interest in HIF-1α as an anticancer drug target. Benzophenone-1B ([4-(1H-benzimidazol-2-ylmethoxy)-3,5-dimethylphenyl]-(4-methoxyphenyl) methanone, or BP-1B) is a new antineoplastic agent with potential angiopreventive effects. Current investigation reports the cellular biochemical modulation underlying BP-1B cytotoxic/antiangiogenic effects. Experimental evidences postulate that BP-1B exhibits the tumour specific cytotoxic actions against various cancer types with prolonged action. Moreover BP-1B efficiently counteracts endothelial cell capillary formation in in-vitro, in-vivo non-tumour and tumour angiogenic systems. Molecular signaling studies reveal that BP-1B arrests nuclear translocation of HIF-1α devoid of p42/44 pathway under CoCl2 induced hypoxic conditions in various cancer cells thereby leading to abrogated HIF-1α dependent activation of VEGF-A, Flt-1, MMP-2, MMP -9 and Ang-1 angiogenic factors resulting in retarded cell migration and invasions. The in-vitro results were reproducible in the reliable in-vivo solid tumour model. Taken together, we conclude that BP-1B impairs angiogenesis by blocking nuclear localization of HIF-1α which can be translated into a potent HIF-1α inhibitor.


Assuntos
Benzofenonas/farmacologia , Núcleo Celular/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias/patologia , Animais , Linhagem Celular Tumoral , Embrião de Galinha , Modelos Animais de Doenças , Progressão da Doença , Células Endoteliais da Veia Umbilical Humana , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Transporte Proteico , Ratos , Fator A de Crescimento do Endotélio Vascular/farmacologia
14.
Angiogenesis ; 20(1): 55-71, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27743086

RESUMO

Hypoxia is a feature of all solid tumours, contributing to tumour progression. Activation of HIF-1α plays a critical role in promoting tumour angiogenesis and metastasis. Since its expression is positively correlated with poor prognosis for cancer patients, HIF-1α is one of the most convincing anticancer targets. BP-1T is a novel antiproliferative agent with promising antiangiogenic effects. In the present study, the molecular mechanism underlying cytotoxic/antiangiogenic effects of BP-1T on tumour/non-tumour angiogenesis was evaluated. Evidences show that BP-1T exhibits potent cytotoxicity with prolonged activity and effectively regressed neovessel formation both in reliable non-tumour and tumour angiogenic models. The expression of CoCl2-induced HIF-1α was inhibited by BP-1T in various p53 (WT)-expressing cancer cells, including A549, MCF-7 and DLA, but not in mutant p53-expressing SCC-9 cells. Mechanistically, BP-1T mediates the HIF-1α proteasomal degradation by activating p53/MDM2 pathway and thereby downregulated HIF-1α-dependent angiogenic genes such as VEGF-A, Flt-1, MMP-2 and MMP-9 under hypoxic condition of in vitro and in vivo solid tumour, eventually leading to abolition of migration and invasion. Based on these observations, we conclude that BP-1T acts on HIF-1α degradation through p53/MDM2 proteasome pathway.


Assuntos
Inibidores da Angiogênese/farmacologia , Benzofenonas/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Tiazóis/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Animais , Benzofenonas/química , Carcinogênese/metabolismo , Carcinogênese/patologia , Morte Celular/efeitos dos fármacos , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Modelos Animais de Doenças , Progressão da Doença , Regulação da Expressão Gênica/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Camundongos , Microvasos/patologia , Modelos Biológicos , Neovascularização Fisiológica/efeitos dos fármacos , Ratos , Transdução de Sinais/efeitos dos fármacos , Tiazóis/química
15.
Int Immunopharmacol ; 39: 158-171, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27475665

RESUMO

Lifestyle and dietary modifications have contributed much to somatic genetic alteration which has concomitantly led to increase in malignant diseases. Henceforth, plant based and dietary interventions to mitigate and impede oncogenic transformation are in great demand. We investigated the latex sap (LSL) of the dietary Lagenaria siceraria vegetable, the first domesticated plant species with the potent lectin activity for its functional role against the tumor progression and its mechanism. LSL has markedly stimulated proliferation of lymphocytes and displayed strong cytotoxic activity against cancer both in-vitro and in-vivo. The tumor regression was paralleled with drastic reduction in tumoral neovasculature as evidenced from angiogenic parameters and abrogated related gene expressions. LSL has also triggered apoptotic signaling cascade in cancer cells through activation of caspase-3 mediated activation of endonuclease and inducing apoptotic cellular events. Collectively our study provides tangible evidences that latex sap from L. siceraria with immunopotentiating ability significantly regresses the tumor progression by targeting angiogenesis and inducing cell death.


Assuntos
Aorta/efeitos dos fármacos , Cucurbitaceae/imunologia , Látex/uso terapêutico , Linfócitos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Lectinas de Plantas/uso terapêutico , Animais , Aorta/fisiologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Linfócitos/fisiologia , Células MCF-7 , Camundongos , Células NIH 3T3 , Transplante de Neoplasias , Técnicas de Cultura de Órgãos , Ratos , Carga Tumoral/efeitos dos fármacos
16.
Eur J Med Chem ; 115: 342-51, 2016 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-27027818

RESUMO

A series of diamide-coupled benzophenone, 2-(4-benzoyl-phenoxy)-N-{2-[2-(4-benzoyl-phenoxy)-acetylamino]-phenyl}-acetamide analogues (9a-l) were synthesized by multistep reactions and all compounds were well characterized. Among the series (9a-l), compound 9k with three methyl groups at ortho position in rings A, B, and D and bromo group at the para position in ring E was selected as a lead compound by screening through multiple cancer cell types by in-vitro cytotoxic and antiproliferative assay systems. Also, the cytotoxic nature of the compound 9k resulted the regression of the tumor growth in-vivo, which could be due to decreased vascularisation in the peritoneum lining of the mice which regress the tumor growth. The results were reconfirmed in-vivo chorioallantoic membrane model which indicates a scope of developing 9k into potent anticancer drug in near future.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Benzofenonas/química , Benzofenonas/farmacologia , Animais , Antineoplásicos/síntese química , Benzofenonas/síntese química , Humanos , Células MCF-7 , Camundongos , Relação Estrutura-Atividade
17.
Eur J Med Chem ; 114: 153-61, 2016 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-26974382

RESUMO

Mitogenicity is the ability of the natural or synthetic compounds to induce cell division or proliferation. A series of salicylic acid derivatives containing isoxazoline moiety (8a-j) were synthesized and their immunopharmacological activities targeting lymphocyte proliferation and angiogenesis were evaluated. The compounds 8a-j mitogenicity were investigated on immunological cells that include human peripheral blood lymphocytes and murine splenocytes in-vitro. The results implicate that among the series of 8a-j, compound 8e showed a potent proliferative response on both human and murine lymphocytes. The proliferative index of the compound 8e was comparable to the reference mitogen Con A and mitogenecity is due to increased secretion IL-2. In -vivo CAM and rat corneal angiogenesis assays were performed to assess the compound's effect on endothelial cell migration and proliferation which inferred that 8e also induces the proliferation of endothelial cells. The study reports the synthetic immunostimulatory and pro-angiogenic activity of novel mitogen 8e which could be translated into new drug in future.


Assuntos
Indutores da Angiogênese/farmacologia , Fatores Imunológicos/farmacologia , Isoxazóis/farmacologia , Neovascularização Fisiológica/efeitos dos fármacos , Ácido Salicílico/farmacologia , Adolescente , Adulto , Indutores da Angiogênese/síntese química , Indutores da Angiogênese/química , Animais , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/imunologia , Células HEK293 , Humanos , Fatores Imunológicos/síntese química , Fatores Imunológicos/química , Isoxazóis/química , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Masculino , Camundongos , Pessoa de Meia-Idade , Estrutura Molecular , Neovascularização Fisiológica/imunologia , Ratos , Ácido Salicílico/química , Baço/efeitos dos fármacos , Baço/imunologia , Relação Estrutura-Atividade , Adulto Jovem
18.
Bioorg Chem ; 65: 110-7, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26918263

RESUMO

A novel series of benzoic acid N'-[2-(4-benzothiazol-2-yl-piperazin-1-yl)-acetyl]-hydrazides 6a-j were synthesized and characterized by IR, (1)H, (13)C NMR, elemental and mass spectral analyses. The in-vitro cytotoxicity and cell viability assay of the synthesized compounds 6a-j were evaluated against Dalton's lymphoma ascites (DLA) cells. Our results showed that compound 6c with a bromo group on phenyl ring has showed promising antiproliferative efficacy. Further investigation of compound 6c on in-vivo treatment model depicts the increased tumor suppression through inhibition of angiogenesis.


Assuntos
Antineoplásicos/farmacologia , Hidrazinas/farmacologia , Linfoma/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Piperazinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Hidrazinas/síntese química , Hidrazinas/química , Linfoma/patologia , Masculino , Camundongos , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Neovascularização Patológica/patologia , Piperazinas/síntese química , Piperazinas/química , Células Tumorais Cultivadas
19.
Bioorg Chem ; 65: 73-81, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26874345

RESUMO

A series of benzophenones possessing pyridine nucleus 8a-l were synthesized by multistep reaction sequence and evaluated for antiproliferative activity against DLA cells by in vitro and in vivo studies. The results suggested that, compounds 8b with fluoro group and 8e with chloro substituent at the benzoyl ring of benzophenone scaffold as well as pyridine ring with hydroxy group exhibited significant activity. Further investigation in mouse model suggests that compounds 8b and 8e have the potency to activate caspase activated DNase (endonuclease) which is responsible for DNA fragmentation, a primary hallmark of apoptosis and thereby inhibits the Dalton's lymphoma ascites tumour growth.


Assuntos
Benzofenonas/farmacologia , Caspases/metabolismo , Núcleo Celular/efeitos dos fármacos , Desoxirribonucleases/metabolismo , Linfoma/genética , Linfoma/patologia , Piridinas/química , Piridinas/farmacologia , Animais , Benzofenonas/síntese química , Benzofenonas/química , Núcleo Celular/enzimologia , Núcleo Celular/patologia , Proliferação de Células/efeitos dos fármacos , Fragmentação do DNA/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Feminino , Humanos , Camundongos , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Piridinas/síntese química , Células Tumorais Cultivadas
20.
Bioorg Chem ; 60: 136-46, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26005956

RESUMO

A series of oxadiazole derivatives possessing morpholine 6a-l were synthesized by nucleophilic substitution reaction of key intermediates [1,3,4]-oxadiazole-2-thiol derivatives 5a-l with 4-(2-chloroethyl) morpholine. Compounds 6a-l were evaluated for their in vitro and in vivo antitumor potential in Dalton's Lymphoma Ascites (DLA) tumor cells. Among 6a-l series, compound 6a with concentration ∼8.5µM have shown extensive cytotoxicity in vitro and 85% reduction in tumor volume in vivo, attributing an excellent anti-proliferative capability towards the cancer cells. Compound 6a has extensively inhibited the Microvessel Density (MVD) or tumoral neovasculature which was evident from the CD31 immuno staining and peritoneal H&E staining. The major reason for the antiproliferative activity of compound 6a was due to the repression of tumor vasculature.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/uso terapêutico , Linfoma/tratamento farmacológico , Microvasos/efeitos dos fármacos , Morfolinas/uso terapêutico , Neovascularização Patológica/tratamento farmacológico , Oxidiazóis/uso terapêutico , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Ascite/tratamento farmacológico , Ascite/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Linfoma/patologia , Camundongos , Microvasos/patologia , Morfolinas/síntese química , Morfolinas/química , Neovascularização Patológica/patologia , Oxidiazóis/síntese química , Oxidiazóis/química
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...