Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 33
Filtrar
Mais filtros

Base de dados
Tipo de documento
Intervalo de ano de publicação
1.
Semin Cancer Biol ; 35 Suppl: S199-S223, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25865775

RESUMO

Cancer arises in the context of an in vivo tumor microenvironment. This microenvironment is both a cause and consequence of tumorigenesis. Tumor and host cells co-evolve dynamically through indirect and direct cellular interactions, eliciting multiscale effects on many biological programs, including cellular proliferation, growth, and metabolism, as well as angiogenesis and hypoxia and innate and adaptive immunity. Here we highlight specific biological processes that could be exploited as targets for the prevention and therapy of cancer. Specifically, we describe how inhibition of targets such as cholesterol synthesis and metabolites, reactive oxygen species and hypoxia, macrophage activation and conversion, indoleamine 2,3-dioxygenase regulation of dendritic cells, vascular endothelial growth factor regulation of angiogenesis, fibrosis inhibition, endoglin, and Janus kinase signaling emerge as examples of important potential nexuses in the regulation of tumorigenesis and the tumor microenvironment that can be targeted. We have also identified therapeutic agents as approaches, in particular natural products such as berberine, resveratrol, onionin A, epigallocatechin gallate, genistein, curcumin, naringenin, desoxyrhapontigenin, piperine, and zerumbone, that may warrant further investigation to target the tumor microenvironment for the treatment and/or prevention of cancer.


Assuntos
Carcinogênese/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Microambiente Tumoral/genética , Antineoplásicos/uso terapêutico , Carcinogênese/genética , Proliferação de Células/efeitos dos fármacos , Humanos , Terapia de Alvo Molecular , Neoplasias/genética , Neoplasias/prevenção & controle , Neovascularização Patológica/genética , Neovascularização Patológica/prevenção & controle , Transdução de Sinais , Microambiente Tumoral/efeitos dos fármacos
2.
Semin Cancer Biol ; 35 Suppl: S151-S184, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25951989

RESUMO

Cancers harbor significant genetic heterogeneity and patterns of relapse following many therapies are due to evolved resistance to treatment. While efforts have been made to combine targeted therapies, significant levels of toxicity have stymied efforts to effectively treat cancer with multi-drug combinations using currently approved therapeutics. We discuss the relationship between tumor-promoting inflammation and cancer as part of a larger effort to develop a broad-spectrum therapeutic approach aimed at a wide range of targets to address this heterogeneity. Specifically, macrophage migration inhibitory factor, cyclooxygenase-2, transcription factor nuclear factor-κB, tumor necrosis factor alpha, inducible nitric oxide synthase, protein kinase B, and CXC chemokines are reviewed as important antiinflammatory targets while curcumin, resveratrol, epigallocatechin gallate, genistein, lycopene, and anthocyanins are reviewed as low-cost, low toxicity means by which these targets might all be reached simultaneously. Future translational work will need to assess the resulting synergies of rationally designed antiinflammatory mixtures (employing low-toxicity constituents), and then combine this with similar approaches targeting the most important pathways across the range of cancer hallmark phenotypes.


Assuntos
Antineoplásicos/uso terapêutico , Inflamação/tratamento farmacológico , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Transformação Celular Neoplásica/efeitos dos fármacos , Heterogeneidade Genética/efeitos dos fármacos , Humanos , Inflamação/genética , Inflamação/patologia , Terapia de Alvo Molecular , Neoplasias/genética , Neoplasias/patologia , Transdução de Sinais/efeitos dos fármacos
3.
Semin Cancer Biol ; 35 Suppl: S78-S103, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25936818

RESUMO

Apoptosis or programmed cell death is natural way of removing aged cells from the body. Most of the anti-cancer therapies trigger apoptosis induction and related cell death networks to eliminate malignant cells. However, in cancer, de-regulated apoptotic signaling, particularly the activation of an anti-apoptotic systems, allows cancer cells to escape this program leading to uncontrolled proliferation resulting in tumor survival, therapeutic resistance and recurrence of cancer. This resistance is a complicated phenomenon that emanates from the interactions of various molecules and signaling pathways. In this comprehensive review we discuss the various factors contributing to apoptosis resistance in cancers. The key resistance targets that are discussed include (1) Bcl-2 and Mcl-1 proteins; (2) autophagy processes; (3) necrosis and necroptosis; (4) heat shock protein signaling; (5) the proteasome pathway; (6) epigenetic mechanisms; and (7) aberrant nuclear export signaling. The shortcomings of current therapeutic modalities are highlighted and a broad spectrum strategy using approaches including (a) gossypol; (b) epigallocatechin-3-gallate; (c) UMI-77 (d) triptolide and (e) selinexor that can be used to overcome cell death resistance is presented. This review provides a roadmap for the design of successful anti-cancer strategies that overcome resistance to apoptosis for better therapeutic outcome in patients with cancer.


Assuntos
Apoptose/genética , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/genética , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Autofagia/genética , Proliferação de Células/genética , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Neoplasias/patologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
4.
Invest New Drugs ; 31(3): 545-57, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23129310

RESUMO

Withaferin A (WA), a steroidal lactone derived from the plant Vassobia breviflora, has been reported to have anti-proliferative, pro-apoptotic, and anti-angiogenic properties against cancer growth. In this study, we identified several key underlying mechanisms of anticancer action of WA in glioblastoma cells. WA was found to inhibit proliferation by inducing a dose-dependent G2/M cell cycle arrest and promoting cell death through both intrinsic and extrinsic apoptotic pathways. This was accompanied by an inhibitory shift in the Akt/mTOR signaling pathway which included diminished expression and/or phosphorylation of Akt, mTOR, p70 S6K, and p85 S6K with increased activation of AMPKα and the tumor suppressor tuberin/TSC2. Alterations in proteins of the MAPK pathway and cell surface receptors like EGFR, Her2/ErbB2, and c-Met were also observed. WA induced an N-acetyl-L-cysteine-repressible enhancement in cellular oxidative potential/stress with subsequent induction of a heat shock stress response primarily through HSP70, HSP32, and HSP27 upregulation and HSF1 downregulation. Taken together, we suggest that WA may represent a promising chemotherapeutic candidate in glioblastoma therapy warranting further translational evaluation.


Assuntos
Antineoplásicos/farmacologia , Glioblastoma/metabolismo , Vitanolídeos/farmacologia , Animais , Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proteínas de Ligação a DNA , Fatores de Transcrição de Choque Térmico , Proteínas de Choque Térmico/metabolismo , Resposta ao Choque Térmico/efeitos dos fármacos , Humanos , Camundongos , Estresse Oxidativo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Fatores de Transcrição
5.
Ann Surg Oncol ; 19 Suppl 3: S483-90, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21837531

RESUMO

BACKGROUND: Current therapies for HNSCC, especially platinum agents, are limited by their toxicities and drug resistance. This study evaluates a novel C-terminal Hsp90 inhibitor (CT-Hsp90-I) for efficacy and toxicity in vitro and in vivo in an orthotopic HNSCC model. Our hypothesis is that C-terminal inhibitors exhibit improved toxicity/efficacy profiles over standard therapies and may represent a novel group of anticancer agents. METHODS: MDA-1986 HNSCC cells were treated with doses of 17-AAG or KU363 (a CT-Hsp90-I) and compared for antiproliferation by GLO-Titer and trypan blue exclusion and for apoptosis by PARP cleavage and caspase-3 inactivation by Western analysis. In vivo studies in Nu/Nu mice examined an orthotopic model of MDA-1986 cells followed by drug dosing intraperitoneally for a 21-day period (mg/kg/dose: cisplatin = 3.5, low-dose KU363 = 5, high-dose KU363 = 25, 17-AAG = 175). Tumor size, weight, and toxicity (body score) were measured 3×/week. RESULTS: The IC(50) levels for KU363 = 1.2-2 µM in MDA-1986. KU363 induces apoptosis at 1 µM with cleavage of PARP and inactivation of caspase-3 levels after 24 h. Client proteins Akt and Raf-1 were also downregulated at 1-3 µM of drug. In vivo, 100% of controls had progressive disease, while 100% of cisplatin animals showed some response, all with significant systemic toxicity. High-dose KU363 showed 88% of animals responding and low-dose KU363 showed 75% responding. KU363 animals showed significantly less toxicity (P < 0.01) than cisplatin or 17-AAG. CONCLUSION: This novel CT-Hsp90-I KU363 manifests potent anticancer activity against HNSCC, showing excellent in vivo efficacy and reduced toxicity compared with standard agents justifying future translational evaluation.


Assuntos
Antineoplásicos/farmacologia , Benzoquinonas/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Lactamas Macrocíclicas/farmacologia , Neoplasias Bucais/tratamento farmacológico , Animais , Antineoplásicos/uso terapêutico , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Benzoquinonas/uso terapêutico , Benzoquinonas/toxicidade , Carcinoma de Células Escamosas/enzimologia , Caspase 3/efeitos dos fármacos , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/uso terapêutico , Cisplatino/toxicidade , Regulação para Baixo/efeitos dos fármacos , Fibroblastos , Humanos , Concentração Inibidora 50 , Lactamas Macrocíclicas/uso terapêutico , Lactamas Macrocíclicas/toxicidade , Camundongos , Neoplasias Bucais/enzimologia , Poli(ADP-Ribose) Polimerases/efeitos dos fármacos , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-raf/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-raf/metabolismo
6.
Tumour Biol ; 33(4): 1179-89, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22477711

RESUMO

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. While effective therapy exists for the primary tumor, there is a lack of effective treatment for metastatic disease currently. Natural withanolide withaferin A (WA) has shown efficacy in cancers demonstrating upregulation of pro-survival pathways. The purpose of the present study is to investigate the effect of WA as a potential therapeutic agent for UM in vitro as well as in vivo. UM cells were treated with WA and several cell-based assays, such as MTS, trypan blue exclusion assay, clonogenic, wound healing, cell cycle shift, annexin V/propidium iodide, and Western blot, were performed. In vivo experiments utilized the 92.1 cells in a xenograft murine model. WA inhibits cell proliferation of uveal melanoma cells with an IC50 of 0.90, 1.66, and 2.42 µM for OMM2.3, 92.1, and MEL290 cells, respectively. Flow cytometry analysis demonstrates G2/M cell cycle arrest and apoptosis at 1 µM WA in treated cells. WA induced apoptosis partly through the suppression of c-Met, Akt, and Raf-1 signaling activation. In vivo studies using WA reduced tumor growth in 100% of animals (p = 0.015). Our observation indicates that WA is a potent drug that inhibits cell proliferation, shifts cell cycle arrest, and induces apoptosis in multiple UM cell lines in vitro. WA-mediated apoptosis in UM cells is partly mediated though the suppression of c-Met and Akt activation. WA significantly decreases UM tumor growth in vivo and justifies further evaluation of this drug for the treatment of metastatic uveal melanoma.


Assuntos
Apoptose/efeitos dos fármacos , Melanoma/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Neoplasias Uveais/tratamento farmacológico , Vitanolídeos/farmacologia , Animais , Western Blotting , Caspase 3/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Feminino , Humanos , Concentração Inibidora 50 , Melanoma/metabolismo , Melanoma/patologia , Camundongos , Camundongos SCID , Estrutura Molecular , Fatores de Tempo , Carga Tumoral/efeitos dos fármacos , Neoplasias Uveais/metabolismo , Neoplasias Uveais/patologia , Vitanolídeos/química , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Gynecol Oncol ; 124(3): 606-12, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22188785

RESUMO

OBJECTIVE: Withaferin A, a natural withanolide, has shown anti-cancer properties in various cancers including breast cancer, but its effects in ovarian cancer remain unexplored. Notch 1 and Notch3 are critically involved in ovarian cancer progression. We decided to examine the effects of Withaferin A in ovarian carcinoma cell lines and its molecular mechanism of action including its regulation of Notch. METHODS: The effects of Withaferin A were examined in CaOV3 and SKOV3 ovarian carcinoma cell lines using MTS assay, clonogenic assay, annexin V/propidium iodide flow cytometry, and cell cycle analysis. Western analysis was conducted to examine the molecular mechanisms of action. RESULTS: Withaferin A inhibited the growth and colony formation of CaOV3 and SKOV3 cells by inducing apoptosis and cell cycle arrest. These changes correlated with down-regulation of Notch1, Notch3, cdc25C, total and phosphorylated Akt, and bcl-2 proteins. CONCLUSIONS: Withaferin A inhibits CaOV3 and SKOV3 ovarian carcinoma cell growth, at least in part by targeting Notch1 and Notch3.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias Ovarianas/tratamento farmacológico , Vitanolídeos/farmacologia , Processos de Crescimento Celular/efeitos dos fármacos , Regulação para Baixo , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Proteína Oncogênica v-akt/antagonistas & inibidores , Proteína Oncogênica v-akt/metabolismo , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptor Notch1/antagonistas & inibidores , Receptor Notch1/metabolismo , Receptor Notch3 , Receptores Notch/antagonistas & inibidores , Receptores Notch/metabolismo , Fosfatases cdc25/metabolismo
8.
Pure Appl Chem ; 84(6): 1353-1367, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-24098060

RESUMO

As part of our search for bioactive compounds from plant biodiversity, 29 withanolides (1, 3-6, 9, 12-18, and 20-35) were recently isolated from three members of the Solanaceae: Physalis longifolia, Vassobia breviflora, and Withania somnifera. Six derivatives (2, 7, 8, 10, 11, and 19) were prepared from these naturally occurring withanolides. All compounds (1-35) were evaluated for in vitro anti-proliferative activity against an array of cell lines [melanoma cell lines (B16F10, SKMEL28); human head and neck squamous cell carcinomas (HNSCC) cell lines (JMAR, MDA1986, DR081-1); breast cancer cell line (Hs578T), and non-malignant human cell line (MRC5)]. This led to the discovery of 15 withanolides, with IC50 values in the range of 0.067-17.4 µM, including withaferin A 1, withaferin A 4,27-diacetate 2, 27-O-glucopyranosylwithaferin A 3, withalongolide H 4, withalongolide C 5, withalongolide A 6, withalongolide A 4,27-diacetate 7, withalongolide A 4,19,27-triacetate 8, withalongolide B 9, withalongolide B 4-acetate 10, withalongolide B 4,19-diacetate 11, withalongolide D 16, withalongolide E 17, withalongolide G 21, and 2,3-dihydrowithaferin A 3-O-sulfate 22). In order to update the growing literature on withanolides and their activities, we summarized the distribution, structural types and anti-proliferative activities for all published withanolides to date. The structure-activity relationship analysis (SARA) confirmed the importance of the presence of a Δ2-1-oxo- functionality in ring A, a 5ß,6ß-epoxy or 5α-chloro-6ß-hydroxy groupings in ring B, and nine carbon side chain with a lactone moiety for cytotoxic activity. Conversely, the SARA indicated that the -OH or -OR groups at C-4, 7, 11, 12, 14, 15, 16, 17, 18, 19, 20, 23, 24, 27, 28 were not contributors to the observed anti-proliferative activity within the systems analyzed.

9.
Chem Pharm Bull (Tokyo) ; 60(10): 1234-9, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23036966

RESUMO

In our recent publication on bioactive guided isolation of compounds from Physalis longifolia (Solanaceae) novel anti-proliferative agents withalongolides A (4) and B (5), and their highly cytotoxic analogues, withalongolide A 4,19,27-triacetate (4a) and withalongolide B 4,19-diacetate (5a) were elucidated. In this study, the two lead compounds (4, 5) were re-isolated in gram quantities for the purpose of further analogue preparation and in vivo testing that would continue to probe structure-activity relationships. During this process, two additional withanolides, named withalongolides O (1) and P (2), were elucidated. Their structures were determined by spectroscopic techniques with 1 being subsequently confirmed by X-ray crystallographic analysis. Utilizing a MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] viability assay, withalongolide O (1) and its 4,7-diaceatate (1a), both containing the functionalities of Δ(2)-1-oxo- in A ring, a 5ß,6ß-epoxy in B ring, and a lactone ring in the nine-carbon side chain, exhibited potent cytotoxicity against human head and neck squamous cell carcinoma (JMAR and MDA-1986), melanoma (B16F10 and SKMEL-28), and normal fetal lung fibroblast (MRC-5) cells with IC(50) values in the range between 0.15 and 2.95 µM. In addition, the previously reported α orientation of 7-acetate group in acnistins C and D should be revised to the ß orientation on the basis of NMR data comparison.


Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Physalis/química , Vitanolídeos/química , Vitanolídeos/farmacologia , Antineoplásicos Fitogênicos/isolamento & purificação , Carcinoma de Células Escamosas/tratamento farmacológico , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Melanoma/tratamento farmacológico , Modelos Moleculares , Carcinoma de Células Escamosas de Cabeça e Pescoço , Relação Estrutura-Atividade , Vitanolídeos/isolamento & purificação
10.
J Nat Prod ; 74(3): 477-82, 2011 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-21314099

RESUMO

Bioassay-guided fractionation of a CH(2)Cl(2)-MeOH extract of the aerial parts of Albizia inundata resulted in the isolation of two new natural oleanane-type triterpene saponins {3-O-[α-L-arabinopyranosyl(1→6)]-2-acetamido-2-deoxy-ß-D-glucopyranosyl oleanolic acid (1) and 3-O-[α-L-arabinopyranosyl(1→2)-α-L-arabinopyranosyl(1→6)]-2-acetamido-2-deoxy-ß-D-glucopyranosyl acacic acid lactone (2)} along with seven known saponins {3-O-[α-L-arabinopyranosyl(1→6)]-2-acetamido-2-deoxy-ß-D-glucopyranosyl echinocystic acid (3), 3-O-[ß-D-xylopyranosyl (l→2)-α-L-arabinopyranosyl(l→6)]-2-acetamido-2-deoxy-ß-D-glucopyranosyl acacic acid lactone (concinnoside D) (4), 3-O-[ß-D-glucopyranosyl(l→2)]-ß-D-glucopyranosyl oleanolic acid (5), 3-O-[α-L-arabinopyranosyl(1→2)-α-L-arabinopyranosyl(l→6)]-ß-D-glucopyranosyl oleanolic acid (6), 3-O-[ß-D-xylopyranosyl(1→2)-α-L-arabinopyranosyl(l→6)]-ß-D-glucopyranosyl oleanolic acid (7), 3-O-[α-L-arabinopyranosyl(l→2)-α-L-arabinopyranosyl(1→6)-[ß-D-glucopyranosyl(l→2)]-ß-D-glucopyranoside echinocystic acid (8), and 3-O-[ß-D-xylopyranosyl(l→2)-α-L-arabinopyranosyl(1→6)-[ß-D-glucopyranosyl(l→2)]-ß-D-glucopyranoside echinocystic acid (9)}. The structures of 1 and 2 were established on the basis of extensive 2D NMR ((1)H-(1)H COSY or DQF-COSY, HSQC, HMBC, TOCSY, and HSQC-TOCSY) spectroscopic, ESIMS, and chemical methods. Saponins 1, 3, 6, and 7 showed cytotoxicity against human head and neck squamous cells (JMAR, MDA1986) and melanoma cells (B16F10, SKMEL28) with IC(50) values in the range 1.8-12.4 µM, using the MTS assay.


Assuntos
Albizzia/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/isolamento & purificação , Saponinas/isolamento & purificação , Antineoplásicos Fitogênicos/química , Argentina , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Ácido Oleanólico/química , Ácido Oleanólico/farmacologia , Saponinas/química , Saponinas/farmacologia , Estereoisomerismo
11.
J Nat Prod ; 74(12): 2532-44, 2011 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-22098611

RESUMO

Fourteen new withanolides, 1-14, named withalongolides A-N, respectively, were isolated from the aerial parts of Physalis longifolia together with eight known compounds (15-22). The structures of compounds 1-14 were elucidated through spectroscopic techniques and chemical methods. In addition, the structures of withanolides 1, 2, 3, and 6 were confirmed by X-ray crystallographic analysis. Using a MTS viability assay, eight withanolides (1, 2, 3, 7, 8, 15, 16, and 19) and four acetylated derivatives (1a, 1b, 2a, and 2b) showed potent cytotoxicity against human head and neck squamous cell carcinoma (JMAR and MDA-1986), melanoma (B16F10 and SKMEL-28), and normal fetal fibroblast (MRC-5) cells with IC50 values in the range between 0.067 and 9.3 µM.


Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Physalis/química , Vitanolídeos/isolamento & purificação , Vitanolídeos/farmacologia , Antineoplásicos Fitogênicos/química , Carcinoma de Células Escamosas , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Kansas , Conformação Molecular , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Vitanolídeos/química
12.
BMC Complement Altern Med ; 11: 84, 2011 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-21978374

RESUMO

BACKGROUND: Withaferin A (WA), a naturally occurring withanolide, induces apoptosis in both estrogen-responsive MCF-7 and estrogen-independent MDA-MB-231 breast cancer cell lines with higher sensitivity in MCF-7 cells, but the underlying mechanisms are not well defined. The purpose of this study was to determine the anti-cancer effects of WA in MCF-7 breast cancer cells and explore alterations in estrogen receptor alpha (ERα) and its associated molecules in vitro as novel mechanisms of WA action. METHODS: The effects of WA on MCF-7 viability and proliferation were evaluated by 3-(4, 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay and trypan blue exclusion assays. Apoptosis was evaluated by Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) flow cytometry and Western blot analysis of poly (ADP-ribose) polymerase (PARP) cleavage. Cell cycle effects were analyzed by PI flow cytometry. Western blotting was also conducted to examine alterations in the expression of ERα and pathways that are associated with ERα function. RESULTS: WA resulted in growth inhibition and decreased viability in MCF-7 cells with an IC50 of 576 nM for 72 h. It also caused a dose- and time-dependent apoptosis and G2/M cell cycle arrest. WA-induced apoptosis was associated with down-regulation of ERα, REarranged during Transfection (RET) tyrosine kinase, and heat shock factor-1 (HSF1), as well as up-regulation of phosphorylated p38 mitogen-activated protein kinase (phospho-p38 MAPK), p53 and p21 protein expression. Co-treatment with protein synthesis inhibitor cycloheximide or proteasome inhibitor MG132 revealed that depletion of ERα by WA is post-translational, due to proteasome-dependent ERα degradation. CONCLUSIONS: Taken together, down-regulation of ERα, RET, HSF1 and up-regulation of phospho-p38 MAPK, p53, p21 are involved in the pro-apoptotic and growth-inhibitory effects of WA in MCF-7 breast cancer cells in vitro. Down-regulation of ERα protein levels by WA is caused by proteasome-dependent ERα degradation.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/genética , Neoplasias da Mama/fisiopatologia , Regulação para Baixo/efeitos dos fármacos , Receptor alfa de Estrogênio/genética , Proteínas Tirosina Quinases/genética , Vitanolídeos/farmacologia , Neoplasias da Mama/enzimologia , Neoplasias da Mama/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Receptor alfa de Estrogênio/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas Tirosina Quinases/metabolismo , Transfecção
13.
Water Environ Res ; 93(5): 714-726, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-32562331

RESUMO

Contamination of water and soil with toxic metals is a serious environmental issue. To study the Pb, Cu, Cd, and Zn sorption behavior by diatomite, batch experiments were carried out with increasing levels of initial concentration (0-200 mg/L) under different contact times (0-360 min) and temperatures (283, 293, 303, and 313 K). The effects of concentration (0-200 mg/L), pH (3-6), and ionic strength (0.01-0.06 mol/L) on the sorption were modeled using response surface methodology (RSM). Results showed that adsorption data were well-fitted by the Langmuir equation. The sorption of metals intensified by increasing initial concentration and pH but ionic strength had inverse effect. High value for R2 (0.99) and adjusted R2 (0.99) showed that the removal of ions can be described by response surface method. One-way ANOVA showed (p-value < 0.0001) that quadratic model is the best model for determining the interaction of variables. The values of the sorption energy parameter from Dubinin-Radushkevich model (E < 8 kJ K-1  mol-1 ) and negative values of ∆G showed that the sorption of the metals was physical and spontaneous. The positive values of enthalpy (ΔH) indicated that the sorption reaction of metals was endothermic at 283-313 K. PRACTITIONER POINTS: Applications of diatomite increased the sorption of Pb, Cd, Zn, and Cu from aqueous solutions. Diatomite, as low-cost adsorbent, had significant potential to sorption of ions. The sorption of heavy metals by adsorbent intensified by increasing initial concentration and pH but ionic strength had inverse effect. High value for R2 (0.99) and adj-R2 (0.99) showed that removal of metals can be described by response surface method (RSM) and the initial concentration of metal was the most significant factor.


Assuntos
Cádmio , Metais Pesados , Adsorção , Terra de Diatomáceas , Concentração de Íons de Hidrogênio , Cinética , Chumbo , Soluções , Termodinâmica , Água , Zinco
14.
Sci Rep ; 11(1): 8009, 2021 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-33850194

RESUMO

Medicinal plants represent a valuable commodity due to beneficial effects of their natural products on human health, prompting a need for finding a way to optimize/increase their production. In this study, a novel growing media with various perlite particle size and its mixture with peat moss was tested for hydroponic-based production of Echinacea purpurea medicinal plant under greenhouse conditions. The plant growth parameters such as plant height, total fresh leave weight, fresh root weight, total biomass, total chlorophyll, leaf area, and essential oil compositions were assessed. Perlite particle size in the growing media was varied from very coarse (more than 2 mm) to very fine (less than 0.5 mm), and the ratio between perlite and peat moss varied from 50:50 v/v to 30:70 v/v. In addition, two nitrate (NO3-) to ammonium (NH4+) ratios (90:10 and 70:30) were tested for each growing media. The medium containing very fine-grade perlite and 50:50 v/v perlite to peat moss ratio was found to be most optimal and beneficial for E. purpurea performance, resulting in maximal plant height, fresh and dry weight, leaf surface area, and chlorophyll content. It was also found that an increase in NO3-/NH4+ ratio caused a significant increase in plant growth parameters and increase the plant essential oil content. The major terpene hydrocarbons found in extract of E. purpurea with the best growth parameters were germacrene D (51%), myrcene (15%), α-pinene (12%), ß-caryophyllene (11%), and 1-Pentadecene (4.4%), respectively. The percentages of these terpene hydrocarbons were increased by increasing of NO3-/NH4+ ratio. It can be concluded that decreasing the perlite particle size and increasing the NO3-/NH4+ ratio increased the plant growth parameters and essential oil compositions in E. purpurea.

15.
Sci Rep ; 11(1): 15202, 2021 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-34312445

RESUMO

Medicinal plants are considered as one of the most important sources of chemical compounds, so preparing a suitable culture media for medicinal plant growth is a critical factor. The present study is aimed to improve the caffeic acid derivatives and alkylamides percentages of Echinacea purpurea root extract in hydroponic culture media with different perlite particle size and NO3-/NH4+ ratios. Perlite particle size in the growing media was varied as very coarse perlite (more than 2 mm), coarse perlite (1.5-2 mm), medium perlite (1-1.5 mm), fine perlite (0.5-1 mm), and very fine perlite (less than 0.5 mm) in different ratios to peat moss (including pure perlite, 50:50 v/v, 30:70 v/v, and pure peat moss). Two NO3-/NH4+ ratios (90:10 and 70:30) were tested in each growing media. All phytochemical analyses were performed according to standard methods using high performance liquid chromatography (HPLC). It was found that the E. purpurea grown in the medium containing very fine-grade perlite with 50:50 v/v perlite to peat moss ratio had the maximum caffeic acid derivatives, including chicoric acid (17 mg g-1 DW), caftaric acid (6.3 mg g-1 DW), chlorogenic acid (0.93 mg g-1 DW), cynarin (0.84 mg g-1 DW), and echinacoside (0.73 mg g-1 DW), as well as, alkylamides (54.21%). The percentages of these phytochemical compounds increased by decreasing perlite particle size and increasing of NO3-/NH4+ ratio. The major alkylamide in the E. purpurea root extract was dodeca-2E, 4E, 8Z-10 (E/Z)-tetraenoic acid isobutylamide in all treatments, ranging from 31.12 to 54.21% of total dry weight. It can be concluded that optimizing hydroponic culture media and nutrient solution has significant effects on E. purpurea chemical compounds.


Assuntos
Óxido de Alumínio , Ácidos Cafeicos/metabolismo , Echinacea/metabolismo , Hidroponia , Compostos de Nitrogênio , Dióxido de Silício , Amidas/metabolismo , Meios de Cultura , Echinacea/crescimento & desenvolvimento , Tamanho da Partícula , Fenóis/metabolismo , Raízes de Plantas/crescimento & desenvolvimento , Raízes de Plantas/metabolismo , Plantas Medicinais/crescimento & desenvolvimento , Plantas Medicinais/metabolismo
16.
J Nat Prod ; 73(9): 1476-81, 2010 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-20726569

RESUMO

As part of a program to discover drug leads from plant biodiversity, the present investigation was undertaken to explore the anticancer potential of compounds derived from selected Latin American plants. Bioassay-guided fractionation of a crude extract of the aerial parts of Vassobia breviflora led to the isolation of the withanolide-type steroidal lactone withaferin A (1). This compound was tested for antiproliferative activity against the head and neck squamous cell carcinoma (HNSCC) cell lines, MDA1986, JMAR, UM-SCC-2, and JHU011. The inhibitory concentrations to reduce cell viability to 50% (IC(50)) were determined by the MTS cytotoxicity assay, and 1 reduced cell viability with IC(50) values in the range 0.5-2.2 µM. A mechanistic study showed that 1 induces apoptosis and cell death in HNSCC cells as well as a cell-cycle shift from G(0)/G(1) to G(2)/M. Cells treated with 1 exhibited inactivation of Akt and a reduction in total Akt concentration. This investigation constitutes the first report of the antiproliferative activity of withaferin A (1) against head and neck squamous carcinoma.


Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Plantas Medicinais/química , Solanaceae/química , Vitanolídeos/isolamento & purificação , Vitanolídeos/farmacologia , Antineoplásicos Fitogênicos/química , Argentina , Ciclo Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Vitanolídeos/química
17.
Sci Rep ; 10(1): 13842, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32796914

RESUMO

Medicinal plant production is most important than other agricultural plants due to their phytochemical compounds effects on human health. Paying attention to plant nutrition requirement is so important. In order to assess the effect of nitrate (NO3-) dosage supplies from two types of fertilizers on growth and phytochemical properties of Echinacea purpurea rhizomata cum radicibus, an experiment with completely simple design was carried out under greenhouse conditions. Two types of fertilizers (new invented nitrogen (N) slow release fertilizer and urea chemical fertilizer) at three dosages (50, 100, and 150 mM) were applied. Plant growth parameters and total phenolic (TPC), total flavonoids (TFC), polysaccarides content, essential oil content, caffeic acid derivatives, and anti-radical scavenging activities of E. purpurea were assessed. The results showed the significant (p ≤ 0.01) differences among treatments, both in growth and phytochemical properties. Using of N slow release, especially in 150 mM dosage, significantly increased all the plant growth and phytochemical properties. The dried E. purpurea rhizomata cum radicibus contained more caftaric acid (max 12.56 mg g-1 DW) and chicoric acid (max 7.56 mg g-1 DW) than other derivatives. Despite the impact of heavy metals on yield and growth of E. purpurea, the concentration of all heavy metals and micronutrients (boron (B), cadmium (Cd), copper (Cu), iron (Fe), manganese (Mn), molybdenum (Mo), nickel (Ni), lead (Pb), and zinc (Zn)) in studied soil and fertilizer samples was less than United States Environmental Protection Agency (USEPA) limits of contamination. Based on the results, using of N slow release fertilizers can improve phytochemical properties of the plant due to its polymeric structure and can be a suitable substitution of chemical fertilizers, especially in medicinal plants growth.


Assuntos
Agricultura/métodos , Echinacea/genética , Echinacea/metabolismo , Fertilizantes , Nitrogênio , Fenômenos Fisiológicos da Nutrição/fisiologia , Compostos Fitoquímicos/metabolismo , Plantas Medicinais , Echinacea/química , Metais Pesados/análise , Micronutrientes/análise , Solo/química
18.
Environ Sci Pollut Res Int ; 25(12): 11614-11625, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29429108

RESUMO

Impact of anthropogenic loading of phosphorous (P) to an aquatic ecosystem can be qualitatively assessed by measuring the buildup and distribution of P in sediments and by differentiating bioavailable and recalcitrant P pools. Distribution of P pools in sediments is affected by the physico-chemical properties including specific elements, particle size distribution, pH, electrical conductivity (EC), and carbonate content. We applied X-ray fluorescence and scanning electron microscopy (SEM) methods to characterize sediments from western rivers in the Urmia Lake basin in Iran with a particular focus on properties that are relevant to P speciation. Phosphorous pools were sequentially extracted into operationally defined exchangeable (EXCH-P), iron and aluminum oxide-bound (Fe/Al-P), calcium-bound (Ca-P), and residual (RES-P) P pools. In river sediments, the size of P pool was found to be in the order of Ca-P > RES-P > Fe/Al-P > EXCH-P indicating small fraction of bioavailable P pool and Ca-P minerals being the most dominant P sink. Carbonate-related properties had an inverse relationship with bioavailable P pools in the river sediments studied. The principal component analysis (PCA) of the sequential extraction data with sediment properties revealed that four principal components described 82.7% of total variation. Similarly, particle size-related properties were found to have the highest eigenvalues in the first PC. Electron diffraction spectra (EDS) and X-ray fluorescence (XRF) analyses showed a largely uniform distribution of P in the upstream sediment. However, limited evidence of local enrichment of P with Fe, Al, and Ca contents was observed in the downstream river sediments. Correlation of Fe/Al-P pool size with Al2O3 and SiO2 contents indicated that P was associated with Al oxide and clay minerals in the sediment matrix. Overall, the results from this study provide insights into the variability of upstream and downstream river processes and their relationship with P pools with regard to their bioavailability. These results are expected to be useful in assessing the potential impact of P loading on the aquatic ecosystem in the Urmia Lake basin.


Assuntos
Monitoramento Ambiental/métodos , Sedimentos Geológicos/química , Fósforo/análise , Rios/química , Poluentes Químicos da Água/análise , Ecossistema , Irã (Geográfico) , Ferro/análise , Minerais/análise , Tamanho da Partícula , Dióxido de Silício/análise
19.
Mol Vis ; 13: 1618-26, 2007 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-17893663

RESUMO

PURPOSE: To determine whether ceramide treatment contributes to reduced cell viability, increased apoptosis, caspase activation, and reactive oxygen species generation in lens epithelial cells. METHODS: Cell viability was determined by the 3-(4,5-dimethylthiozol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptotic cell death was determined by 4,6 diamidino-2-phenylindole (DAPI) nuclear staining. Quantitative DNA fragmentation was determined by specific determination of cytosolic mononucleosomes and oligonucleosome-bound DNA. Caspase-3/7 activation was determined by using the Apo-ONE Assay. Detection of reactive oxygen species was achieved by a carboxy-2,7-dichlorofluorescein diacetate (carboxy-H2DCFDA) staining method and lipid peroxidation assay. RESULTS: C2-ceramide and C6-ceramide reduced primary bovine lens epithelial cell and human lens epithelial cell survival in a dose- and time-dependent manner. The effect of ceramide on cell viability was specific since C2-dihydroceramide, a chemically similar ceramide lacking four to five double-bonds, did not adversely affect lens epithelial cell viability. Release of endogenous natural ceramides by treatment of lens epithelial cells with bacterial sphingomyelinase reduced cell viability. Ceramide-induced apoptosis in lens epithelial cells was determined by nuclear appearance and DNA fragmentation. Apoptosis was induced by exogenous C2-ceramide in a dose-dependent and time-dependent manner and ceramide-mediated apoptosis of lens epithelial cells was associated with caspase-3/7 activation. C2-ceramide treatment resulted in reactive oxygen species generation. CONCLUSIONS: These results suggest that ceramide reduced cell viability and increased apoptosis in a dose-dependent and time-dependent manner in lens epithelial cells. Ceramide-induced oxidative stress suggests that age-related cataracts may be modulated by ceramide levels in the lens.


Assuntos
Ceramidas/farmacologia , Cristalino/efeitos dos fármacos , Cristalino/fisiologia , Esfingosina/análogos & derivados , Animais , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Bovinos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ceramidas/administração & dosagem , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/fisiologia , Humanos , Cristalino/citologia , Cristalino/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Esfingosina/administração & dosagem , Esfingosina/farmacologia , Fatores de Tempo
20.
Enzymes ; 37: 73-94, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26298456

RESUMO

Plant-based Ayurvedic medicine has been practiced in India for thousands of years for the treatment of a variety of disorders. They are rich sources of bioactive compounds potentially useful for prevention and treatment of cancer. Withania somnifera (commonly known as Ashwagandha in Ayurvedic medicine) is a widely used medicinal plant whose anticancer value was recognized after isolation of steroidal compounds withanolides from the leaves of this shrub. Withaferin A is the first member of withanolides to be isolated, and it is the most abundant withanolide present in W. somnifera. Its cancer-protective role has now been established using chemically induced and oncogene-driven rodent cancer models. The present review summarizes the key preclinical studies demonstrating anticancer effects of withaferin along with its molecular targets and mechanisms related to its anticancer effects. Anticancer potential of other withanolides is also discussed.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA