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1.
Am J Chin Med ; 49(1): 181-198, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33371817

RESUMO

Metastasis is the most prevalent cause of cancer-associated deaths amongst patients with cervical cancer. Epithelial-mesenchymal transition (EMT) is essential for carcinogenesis, and it confers metastatic properties to cancer cells. Gossypol is a natural polyphenolic compound with anti-inflammation, anti-oxidant, and anticancer activities. In this study, we investigated the antimetastatic and antitumour effects of gossypol on human cervical cancer cells (HeLa and SiHa cells). Gossypol exerted a strong inhibition effect on the migration and invasion of human cervical cancer cells. It reduced the focal adhesion kinase (FAK) pathway-mediated expression of matrix metalloproteinase-2 and urokinase-type plasminogen activator, subsequently inhibiting the invasion of SiHa cells. In addition, gossypol reversed EMT induced by transforming growth factor beta 1 (TGF-[Formula: see text]1) and up-regulated epithelial markers, such as E-cadherin but significantly suppressed Ras homolog family member (Rho)A, RhoB, and p-Samd3. The tail vein injection model showed that gossypol treatment via oral gavage reduced lung metastasis. Gossypol also decreased tumour growth in vivo in the nude mouse xenograft model. All these findings suggest that gossypol suppressed the invasion and migration of human cervical cancer cells by targeting the FAK signaling pathway and reversing TGF-[Formula: see text]1-induced EMT. Hence, gossypol warrants further attention for basic mechanistic studies and drug development.


Assuntos
Antineoplásicos Fitogênicos , Transição Epitelial-Mesenquimal , Gossipol/farmacologia , Gossipol/uso terapêutico , Metástase Neoplásica/prevenção & controle , Peptídeo Hidrolases/metabolismo , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/etiologia , Animais , Movimento Celular/efeitos dos fármacos , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Gossipol/administração & dosagem , Células HeLa , Xenoenxertos , Humanos , Camundongos Nus , Invasividade Neoplásica , Transplante de Neoplasias , Fitoterapia , Neoplasias do Colo do Útero/patologia
2.
Int J Nanomedicine ; 15: 7415-7431, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33116479

RESUMO

INTRODUCTION: AT101, the R-(-)-enantiomer of the cottonseed-derived polyphenol gossypol, is a promising drug in glioblastoma multiforme (GBM) therapy due to its ability to trigger autophagic cell death but also to facilitate apoptosis in tumor cells. It does have some limitations such as poor solubility in water-based media and consequent low bioavailability, which affect its response rate during treatment. To overcome this drawback and to improve the anti-cancer potential of AT101, the use of cubosome-based formulation for AT101 drug delivery has been proposed. This is the first report on the use of cubosomes as AT101 drug carriers in GBM cells. MATERIALS AND METHODS: Cubosomes loaded with AT101 were prepared from glyceryl monooleate (GMO) and the surfactant Pluronic F-127 using the top-down approach. The drug was introduced into the lipid prior to dispersion. Prepared formulations were then subjected to complex physicochemical and biological characterization. RESULTS: Formulations of AT101-loaded cubosomes were highly stable colloids with a high drug entrapment efficiency (97.7%) and a continuous, sustained drug release approaching 35% over 72 h. Using selective and sensitive NMR diffusometry, the drug was shown to be efficiently bound to the lipid-based cubosomes. In vitro imaging studies showed the high efficiency of cubosomal nanoparticles uptake into GBM cells, as well as their marked ability to penetrate into tumor spheroids. Treatment of GBM cells with the AT101-loaded cubosomes, but not with the free drug, induced cytoskeletal rearrangement and shortening of actin fibers. The prepared nanoparticles revealed stronger in vitro cytotoxic effects against GBM cells (A172 and LN229 cell lines), than against normal brain cells (SVGA and HMC3 cell lines). CONCLUSION: The results indicate that GMO-AT101 cubosome formulations are a promising basic tool for alternative approaches to GBM treatment.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Portadores de Fármacos/química , Glioblastoma/tratamento farmacológico , Gossipol/análogos & derivados , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/farmacocinética , Disponibilidade Biológica , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Coloides/química , Coloides/farmacologia , Citoesqueleto/efeitos dos fármacos , Preparações de Ação Retardada/química , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Glioblastoma/patologia , Glicerídeos/química , Gossipol/administração & dosagem , Gossipol/farmacocinética , Gossipol/farmacologia , Humanos , Lipídeos/química , Espectroscopia de Ressonância Magnética/métodos , Nanopartículas/administração & dosagem , Nanopartículas/química , Poloxâmero/química , Solubilidade
3.
Arq. bras. med. vet. zootec. (Online) ; 72(3): 673-680, May-June, 2020. ilus, tab
Artigo em Português | LILACS, VETINDEX | ID: biblio-1128724

RESUMO

A cotonicultura tem forte fator de impacto na economia nacional, e o estado de Mato Grosso se destaca por ser o maior produtor de algodão herbáceo e deter o maior rebanho bovino do país, condições essas que estimulam o uso do caroço, da torta e do farelo de algodão na alimentação animal. Considerando que o gossipol está presente nos subprodutos do algodão e que seus efeitos sobre a reprodução podem reduzir a fertilidade dos animais, objetivou-se, com essa pesquisa, avaliar o efeito da ingestão de dietas com diferentes teores de gossipol livre por dia sobre a morfometria testicular e a qualidade seminal de touros da raça Nelore. Foram utilizados 28 touros, distribuídos aleatoriamente em seis tratamentos: T0, 0 grama de gossipol livre/touro/dia ; T1, 1,08 grama de gossipol livre/touro/dia; T2, 2,07 gramas de gossipol livre/touro/dia; T3, 3,24 gramas de gossipol livre/touro/dia; T4, 3,82 gramas de gossipol livre/touro/dia e T5, 5,08 gramas de gossipol livre/touro/dia. Os animais de cada tratamento foram mantidos confinados em área média de 100m2, dotada de bebedouro, cochos para mistura mineral e para volumoso/concentrado. O consumo de 3,24 gramas de gossipol livre/touro/dia alterou a qualidade espermática e a morfometria testicular de touros.(AU)


The cotton industry has a strong impact factor in the Brazilian economy and the state of Mato Grosso stands out for being the largest upland-type cotton producer and also holds the largest cattle herd in the country, conditions that stimulate the use of cottonseed pie and cottonseed meal in animal feed. Whereas gossypol is present in cotton by-products and their effects on reproduction can reduce the animal fertility, this research evaluated the effect of diets with different free gossypol contents in the testicular morphometry and semen quality of Nelore bulls. 28 bulls were randomly distributed in six treatments: T0, receiving no free gossypol; T1, receiving 1.08g / bull / day; T2, receiving 2.07g / bull / day; T3, receiving 3.24g / bull / day; T4, receiving 3.82g / bull / day and T5, receiving 5.08g / bull / day of free gossypol respectively. The animals in each treatment were kept confined in an averaged area of 100m2, having fresh water, troughs for mineral mixture and roughage / concentrate. The consumption of 3.24g of free gossypol / bull / day altered the bulls sperm quality and testicular morphometry.(AU)


Assuntos
Animais , Masculino , Bovinos , Testículo/anatomia & histologia , Óleo de Sementes de Algodão/administração & dosagem , Gossipol/administração & dosagem , Análise do Sêmen , Infertilidade Masculina/veterinária
4.
J Cancer Res Clin Oncol ; 146(1): 117-126, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31844979

RESUMO

PURPOSE: Glioblastoma multiforme (GBM) is a poorly curable disease due to its profound chemoresistance. Despite recent advances in surgery, radiotherapy and chemotherapy, the efficient treatment of GBMs is still a clinical challenge. Beside others, AT101, the R-(-) enantiomer of gossypol, and demethoxycurcumin (DMC), a curcumin-related demethoxy compound derived from Curcuma longa, were considered as possible alternative drugs for GBM therapy. METHODS: Using different human primary GBM cell cultures in a long-term stimulation in vitro model, the cytotoxic and anti-proliferative effects of single and combined treatment with 5 µM AT101 and 5 µM or 10 µM DMC were investigated. Furthermore, western blots on pAkt and pp44/42 as well as JC-1 staining and real-time RT-PCR were performed to understand the influence of the treatment at the molecular and gene level. RESULTS: Due to enhanced anti-proliferative effects, we showed that combined therapy with both drugs was superior to a single treatment with AT101 or DMC. Here, by determination of the combination index, a synergism of the combined drugs was detectable. Phosphorylation and thereby activation of the kinases p44/42 and Akt, which are involved in proliferation and survival processes, were inhibited, the mitochondrial membrane potential of the GBM cells was altered, and genes involved in dormancy-associated processes were regulated by the combined treatment strategy. CONCLUSION: Combined treatment with different drugs might be an option to efficiently overcome chemoresistance of GBM cells in a long-term treatment strategy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Diarileptanoides/farmacologia , Glioblastoma/tratamento farmacológico , Gossipol/análogos & derivados , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/farmacologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Proliferação de Células/efeitos dos fármacos , Diarileptanoides/administração & dosagem , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Expressão Gênica/efeitos dos fármacos , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patologia , Gossipol/administração & dosagem , Gossipol/farmacologia , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Células Tumorais Cultivadas
5.
Fish Shellfish Immunol ; 86: 814-831, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30543935

RESUMO

The present study explored the effects of dietary gossypol on the gut health of on-growing grass carp. The fish were fed six diets containing different levels of free gossypol (0, 121.38, 243.94, 363.89, 759.93 and 1162.06 mg/kg diet) from gossypol-acetic acid for 60 days and then challenged with Aeromonas hydrophila for 14 days. The results showed that dietary gossypol (1) could aggravate enteritis and damage the structure of intestinal epithelial cells, (2) decreased the lysozyme (LZ) and Acid phosphatase (ACP) activities, complement 3 (C3), C4 and immunoglobulin M (IgM) contents, and it down-regulated the Hepcidin (rather than distal intestine (DI)), immunoglobulin Z (IgZ), liver-expressed antimicrobial peptide (LEAP)-2B, Mucin2 and ß-defensin-1 mRNA levels in the proximal intestine (PI), mid intestine (MI) and DI, (3) up-regulated intestinal pro-inflammatory cytokines tumor necrosis factor α (TNF-α), interferon γ2 (IFN-γ2), interleukin 1ß (IL-1ß), IL-6 (only in PI), IL-8 and IL-12p35 mRNA levels partly related to nuclear factor kappa B (NF-κB) signalling, and (4) down-regulated the mRNA levels of anti-inflammatory cytokines such as transforming growth factor (TGF)-ß1, TGF-ß2, interleukin 4/13A (IL-4/13A) (except IL-4/13B), IL-10 and IL-11 partly relating to target of rapamycin (TOR) signalling in the intestines of on-growing grass carp. Moreover, the dietary gossypol had no impact on the LEAP-2A, IL-12P40, IL-17D, IL-10, NF-κBp52, IKKα and eIF4E-binding proteins 2 (4E-BP2) mRNA levels in the intestines. Finally, based on the intestinal histopathological results, enteritis morbidity, LZ activity and IgM content, the safe dose of gossypol in the diets for on-growing grass carp should be less than 103.42 mg/kg diet.


Assuntos
Carpas , Doenças dos Peixes/imunologia , Gossipol/análogos & derivados , Imunidade Inata/imunologia , Inflamação/veterinária , Intestinos/imunologia , Aeromonas hydrophila/fisiologia , Ração Animal/análise , Animais , Dieta/veterinária , Suplementos Nutricionais/análise , Relação Dose-Resposta a Droga , Doenças dos Peixes/induzido quimicamente , Doenças dos Peixes/microbiologia , Gossipol/administração & dosagem , Gossipol/metabolismo , Infecções por Bactérias Gram-Negativas/imunologia , Infecções por Bactérias Gram-Negativas/veterinária , Imunidade Inata/efeitos dos fármacos , Inflamação/induzido quimicamente , Inflamação/imunologia , Intestinos/efeitos dos fármacos , Distribuição Aleatória
6.
Theriogenology ; 110: 153-157, 2018 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-29407896

RESUMO

The aim of the present study was to analyze seminal quality of young bulls subjected to different frequencies of gossypol supplementation. Forty-eight Nellore bulls, with 19 months of age and weighing 357.8 ±â€¯7.2 kg, were used in this study. Animals were fed with 10.5 kg of standard supplement containing free-gossypol from whole cottonseed (WCS) at the following frequency: 3x/week (G3x), 5x/week (G5x) or 7x/week (G7x - Control). Additionally, a negative control was provided, and the treated animals received only mineral supplement (MM) ad libtum. The experiment lasted for 84 days and semen was collected at the beginning and at the end for analysis and cryopreservation. Fresh semen was used for initial analysis and plasma membrane integrity and sperm morphology were also determined. General motility using computer assisted sperm analysis (CASA), plasma and acrosomal membranes integrity, mitochondrial activity, and induced oxidative stress were assessed in post-thawed semen. The study design was completely randomized. Parametric data were analyzed by ANOVA and non-parametric data by the Wilcoxon test, using the statistical program SAS. Level of significance was set at 5%. Supplementation with WCS, regardless the frequency, increased total (P = .009) and head (P = .005) defects in comparison to animals receiving only forage and mineral supplement. Infrequent supplementation, particularly 5 times in the week (G5X), increased head (P = .026) and midpiece (P = .014) abnormalities. Sperm motility in fresh semen was lower in animals that received daily supplementation than those supplemented on alternate days (P = .021). Additionally, animals supplemented daily showed lower percentage of spermatozoa with intact acrosome compared to those supplemented on alternate days (P = .005). Thus, regardless the frequency of supplementation, free-gossypol supplementation affects sperm quality. Although the amount of free gossypol supplied weekly was the same among treatments, daily supplementation compromised sperm kinetics, differently from infrequent supplementation that led to sperm defects developed during spermatogenesis.


Assuntos
Ração Animal , Bovinos , Gossipol/administração & dosagem , Gossipol/toxicidade , Reprodução/efeitos dos fármacos , Ração Animal/toxicidade , Fenômenos Fisiológicos da Nutrição Animal , Animais , Criopreservação/métodos , Criopreservação/veterinária , Suplementos Nutricionais , Relação Dose-Resposta a Droga , Esquema de Medicação , Masculino , Sêmen/citologia , Sêmen/efeitos dos fármacos , Análise do Sêmen/veterinária , Preservação do Sêmen/veterinária , Maturidade Sexual/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos
7.
Poult Sci ; 94(10): 2456-63, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26287003

RESUMO

An experiment was conducted to evaluate the application of dietary low-gossypol cottonseed meal (LCSM) in layers' diets. A total of 432 40-week-old Hy-line W36 laying hens were allocated to one of the six dietary treatments with 6 replicates of 12 birds each. The control group was fed a corn-soybean meal basal diet, and the 4 experimental diets consisted of a basal diet with 50, 98.3, 144.2, or 189 g/kg LCSM, respectively (correspondingly 25%, 50%, 75%, 100% dietary protein provided by soybean meal were replaced by LCSM). The sixth group was fed a basal diet supplemented with free gossypol (FG group). The feeding trial lasted for 12 weeks. The results showed that no significant difference was observed on egg production or feed conversion ratio (FCR, feed/egg, g/g) among all groups, but feed intake and egg weight were significantly decreased in the 189 g/kg LCSM group in weeks 46 to 51 (P < 0.05). A significant decrease was not observed in shell strength, shell thickness, and yolk color in all periods, but Haugh unit, albumen height, and egg white protein content were reduced in 189 g/kg LCSM group in weeks 46 to 51 (P < 0.05). No significant differences were found between the control and FG group. There was no obvious difference on plasma levels of total protein, blood urea nitrogen, uric acid, and activities of albumen, alanine aminotransferase, aspartate aminotransferase and the histopathology of liver, kidney, and oviduct in all groups. In conclusion, decreasing feed intake, egg weight, and egg quality were observed in the 189 g/kg LCSM group. However, the adverse effect was not relevant to the presence of FG in LCSM. Dietary LCSM supplementation of 98.3 g/kg was recommended with optimum FCR and without adverse effect on egg production, quality, and health of layers.


Assuntos
Galinhas/metabolismo , Óleo de Sementes de Algodão/metabolismo , Gossipol/metabolismo , Ração Animal/análise , Animais , Análise Química do Sangue/veterinária , Óleo de Sementes de Algodão/administração & dosagem , Dieta/veterinária , Suplementos Nutricionais/análise , Relação Dose-Resposta a Droga , Feminino , Gossipol/administração & dosagem , Óvulo/efeitos dos fármacos , Óvulo/fisiologia , Reprodução/efeitos dos fármacos
8.
Mol Cancer Ther ; 11(2): 416-26, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22188816

RESUMO

The natural BH3-mimetic (-)-gossypol shows promising efficacy in ongoing phase II/III clinical trials for human prostate cancer. Here, we show for the first time, that treatment with (-)-gossypol and multikinase inhibitor sorafenib synergistically suppresses the growth of androgen-independent prostate cancer cells (AI-PC) in vitro and in vivo. Our data suggest that sorafenib attenuates (-)-gossypol-induced Mcl-1 upregulation in AI-PCs. In this way, it serves as a potent chemosensitizer to affect cell death. Interestingly, (-)-gossypol and sorafenib induce cell death via two distinct pathways among different AI-PCs; DU145 cells via apoptosis and PC-3 via autophagy. The appointed death pathway may depend on the level of proapoptotic protein Bak, although the level of antiapoptotic protein Bcl-2 plays some role in it. DU145 cells with high Bak level prefer apoptosis induction, whereas PC-3 cells with low Bak prefer the induction of autophagy. Furthermore, inhibiting nondominant death pathways, that is, autophagy in DU145 and apoptosis in PC-3, enhances cell killing by (-)-gossypol/sorafenib combination therapy. Ultimately, our data expose a new action for sorafenib as an enhancer of (-)-gossypol-induced cell growth suppression and reveal a novel cell death mode by Bak activation manners in AI-PCs. These new insights may facilitate the rational design of clinical trials by selecting patients most likely to benefit from the Bcl-2-targeted molecular therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína Killer-Antagonista Homóloga a bcl-2/metabolismo , Androgênios/metabolismo , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Benzenossulfonatos/administração & dosagem , Benzenossulfonatos/farmacologia , Western Blotting , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Feminino , Gossipol/administração & dosagem , Gossipol/farmacologia , Humanos , Masculino , Camundongos , Camundongos Nus , Proteína de Sequência 1 de Leucemia de Células Mieloides , Niacinamida/análogos & derivados , Compostos de Fenilureia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Piridinas/administração & dosagem , Piridinas/farmacologia , Sorafenibe , Fatores de Tempo , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Pharm Res ; 28(12): 3256-64, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21710341

RESUMO

PURPOSE: We have demonstrated that (-)-gossypol-enriched cottonseed oil [(-)-GPCSO] can down-regulate Bcl-2 expression in MCF-7 and primary cultured human breast cancer epithelial cells (PCHBCECs). However, this agent has not been evaluated in vivo due to its limited solubility. We aimed to develop liposomes containing (-)-GPCSO to suppress Bcl-2/Bcl-xL expression. METHODS: (-)-GPCSO liposomes were prepared and evaluated for effects on breast cancer cell viability, MDA-MB-231 xenograft tumor growth, cellular Bcl-2 and Bcl-xL mRNA levels, and chemosensitivity to paclitaxel. RESULTS: (-)-GPCSO liposomes prepared had excellent stability. Cytotoxicity of (-)-GPCSO liposomes was significantly reduced compared to (-)-GPCSO in culture medium. Bcl-2 and Bcl-xL mRNA expression was down-regulated by (-)-GPCSO in culture medium or (-)-GPCSO liposomes in MDA-MB-231 cells. In PCHBCECs, Bcl-2 and Bcl-xL expression were down-regulated by (-)-GPCSO liposomes. (-)-GPCSO in culture medium induced only a mild reduction in Bcl-xL. In the MDA-MB-231 xenograft tumor model, (-)-GPCSO liposomes exhibited tumor-suppressive activity and significantly reduced intratumoral Bcl-2 and Bcl-xL expression. Cytotoxicity of paclitaxel was increased by pretreatment with (-)-GPCSO liposomes in MDA-MB-231 and PCHBCECs. CONCLUSIONS: Findings suggest that (-)-GPCSO liposomes warrant continued investigation as a chemosensitizer for breast cancers exhibiting Bcl-2-/Bcl-xL-mediated drug resistance.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Óleo de Sementes de Algodão/uso terapêutico , Gossipol/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteína bcl-X/genética , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/farmacologia , Mama/efeitos dos fármacos , Mama/metabolismo , Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Óleo de Sementes de Algodão/administração & dosagem , Óleo de Sementes de Algodão/farmacologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Gossipol/administração & dosagem , Gossipol/farmacologia , Humanos , Lipossomos , Camundongos , Camundongos Nus , Paclitaxel/farmacologia , Células Tumorais Cultivadas
10.
Phytomedicine ; 15(8): 563-5, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18573644

RESUMO

Chronic lymphocytic leukaemia (CLL) results from the accumulation of malignant immunologically incompetent lymphocytes. A routine full blood count of a single patient revealed that he had CLL. The daily intake of 700ml of fresh bovine milk resulted in a decrease in the lymphocyte count from 85.5x10(9)/l to 12.5x10(9)/l over a period of 5 years. The aim was to establish which constituent(s) in milk would be responsible for the decline of the lymphocyte count. It was found that the higher vitamin D constituent in the milk, the lower the lymphocyte count. Whilst the milk from large dairy farms which use supplements in the feed in order to increase milk production, considerably decreased the lymphocyte count, the milk from small dairy farms, which do not supplement, had hardly any effect. The present study indicates that gossypol in cottonseed cake and oil are potentially responsible for the decrease in white blood cell count. It appears that gossypol is a very powerful anti-neoplastic agent. Free gossypol (Fig. 1) is a toxic phenolic compound which becomes detoxified in ruminants by binding to milk proteins, but gossypol is still an active inhibitor of tumour growth in the excreted milk.


Assuntos
Antineoplásicos/uso terapêutico , Gossipol/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leite/química , Ração Animal , Animais , Antineoplásicos/química , Bovinos , Óleo de Sementes de Algodão/química , Esquema de Medicação , Gossipol/administração & dosagem , Gossipol/química , Humanos , Masculino , Estrutura Molecular , Fitoterapia , África do Sul
11.
Leuk Lymphoma ; 48(11): 2204-12, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17926190

RESUMO

Chronic myeloid leukemia (CML) is characterized by the presence of chimeric protein BCR-ABL associated with high tyrosine kinase (TK) activity, which leads to cell tumorogenicity, resistance to apoptosis, and differentiation. Gossypol is a natural polyphenolic compound isolated from cottonseed and has antiproliferative activity in a variety of cancer cell lines. (-)Gossypol is proved the potent component. Here we examined the growth inhibitory effect of (-)gossypol and its combination with imatinib in K562 cells. (-)Gossypol inhibited cell growth, promoted apoptosis, induced DeltaPsim loss, and cytochrome C release. Furthermore, (-)gossypol had a synergistic inhibitory effect on growth in K562 cells when combined with imatinib. Enhanced apoptosis, cytochrome C release, and caspase 3 cleavage as well as noticeable decrease of Mcl-1 and Bcl-XL were observed in K562 cells treated with both (-)gossypol and imatinib. These results suggest that (-)gossypol induced apoptosis in K562 cells through a mitochondria pathway and that the combination of imatinib and (-)gossypol might be an effective treatment for CML.


Assuntos
Apoptose/efeitos dos fármacos , Gossipol/farmacologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Piperazinas/farmacologia , Pirimidinas/farmacologia , Benzamidas , Caspase 3/metabolismo , Proliferação de Células/efeitos dos fármacos , Citocromos c/metabolismo , Regulação para Baixo/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Proteínas de Fusão bcr-abl/metabolismo , Gossipol/administração & dosagem , Humanos , Mesilato de Imatinib , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/enzimologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteína de Sequência 1 de Leucemia de Células Mieloides , Proteínas de Neoplasias/metabolismo , Piperazinas/administração & dosagem , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Pirimidinas/administração & dosagem , Proteína bcl-X/metabolismo
12.
Anticancer Res ; 27(1A): 107-16, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17352222

RESUMO

BACKGROUND: Multidrug resistance (MDR) is a major impediment to successful cancer chemotherapy. P-glycoprotein (P-gp), the product of the multidrug resistance 1 (MDR1) gene, acts as an efflux pump and prevents sufficient intracellular accumulation of several anticancer agents, thus, playing a major role in MDR. Tamoxifen (Tam), ICI 182 780 (ICI) and Adriamycin (Adr) alone or with (-)-gossypol-enriched cottonseed oil [(-)-GPCSO] possible effects on cell growth inhibition and regulation of MDR1, mRNA and P-gp expression were examined in both an MDR human breast cancer cell line, MCF-7/Adr cells, and primary cultured human breast cancer epithelial cells (PCHBCEC). MATERIALS AND METHODS: Cells were treated with 0.05% of (-)-GPCSO either in the absence or presence of either 0.1 microM Tam, ICI or Adr for 24 h. RESULTS: Using the non-radioactive cell proliferation MTS assay, none of these chemotherapeutic agents alone inhibited MCF-7/Adr cell and PCHBCEC proliferation; meanwhile, the combination of 0.1 microM Tam, ICI or Adr with 0.05% (-)-GPCSO significantly reduced MCF-7/Adr cell growth by approximately 34%, 32% and 23%, respectively, of that of the vehicle-treated cells. For PCHBCEC, the combination of 0.05% (-)-GPCSO with 0.1 microM of Tam, ICI and Adr reduced cell growth to about 94%, 90%, and 71% respectively, of the vehicle treated PCHBCEC. Furthermore, (-)-GPCSO inhibited MDR1/P-gp expression in both MCF- 7/Adr and PCHBCEC in a dose-dependent manner. Our results provide insight into the MDR-reversing potential of (-)-GPCSO in human breast cancer cells resistant to current chemotherapeutic agents.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Óleo de Sementes de Algodão/farmacologia , Genes MDR/efeitos dos fármacos , Gossipol/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/biossíntese , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Óleo de Sementes de Algodão/administração & dosagem , Óleo de Sementes de Algodão/química , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacologia , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Estradiol/administração & dosagem , Estradiol/análogos & derivados , Estradiol/farmacologia , Fulvestranto , Expressão Gênica/efeitos dos fármacos , Gossipol/administração & dosagem , Gossipol/química , Humanos , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Tamoxifeno/administração & dosagem , Tamoxifeno/farmacologia , Células Tumorais Cultivadas
13.
J Dairy Sci ; 88(10): 3563-74, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16162530

RESUMO

Four experiments were conducted to evaluate factors influencing concentrations of plasma total gossypol (TG) in 30 Holstein steers fed cottonseed products. At the end of each 28-d experiment, steers were weighed and blood samples were collected and analyzed for plasma TG concentrations. During the entire study, steers did not show any overt signs of gossypol toxicity. In the 28 d before experiment 1, 30 steers with a body weight (BW) of 273 kg were fed a standardization diet with 15.0% Upland whole cottonseed (WCS) that resulted in a mean intake of 9.08 g/d of TG per steer/d and a plasma TG of 1.66 microg/mL. In experiment 1, 30 steers were fed 1 of 5 diets with 15.0% Upland WCS, but different levels of supplemental Fe [0, 150, 300, 450, and 600 mg/kg of diet dry matter (DM)]. Average daily gain was not affected by level of Fe in the diet, but DM intake, plasma TG, and plasma TG response decreased linearly as Fe in diets increased. In experiment 2, steers were fed diets with 15.0% Upland cottonseed as whole, cracked, roasted, cracked-roasted, or extruded. Analysis of the seed revealed that roasting or extrusion markedly reduced free gossypol (FG) content. Minor effects on animal performance were observed, but plasma TG decreased with roasting or extrusion of seeds, with the greatest reduction when the seed was cracked and then roasted. In experiment 3, steers were fed 2 levels of WCS (7.0 or 14.0% of DM) with 3 levels of cottonseed meal (2.8, 5.5, or 8.5% of DM) in the diet. Animal performance was not altered by diet, but plasma gossypol concentrations and responses were greater in steers fed diets with more WCS, because of the greater FG intake. In experiment 4, 24 steers were fed diets with 15.0% cottonseed (Upland or Pima) either as whole or cracked. Pima cottonseed increased TG and FG intakes, which resulted in greater plasma TG concentration and response. Animal response to processing of cottonseed tended to differ according to type of cottonseed. However, feeding Pima and cracking of cottonseed increased gossypol availability and plasma TG concentrations.


Assuntos
Bovinos/sangue , Óleo de Sementes de Algodão , Dieta , Gossipol/administração & dosagem , Gossipol/sangue , Ferro da Dieta/administração & dosagem , Animais , Disponibilidade Biológica , Suplementos Nutricionais , Manipulação de Alimentos , Gossipol/farmacocinética , Masculino , Tamanho da Partícula , Análise de Regressão , Aumento de Peso
14.
Contraception ; 70(4): 335-42, 2004 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15451339

RESUMO

Attempts to develop gossypol and steroidal hormones alone as a male contraceptive have been tested for many years; however, both caused undesirable side effects that have prevented their acceptance. In this study, we formulated a regimen of combined gossypol at a low dose of 12 mg/kg or a high dose of 50 mg/kg plus methyltestosterone 20 mg/kg and ethinylestradiol 100 g/kg daily (12 mg G+H and 50 mg G+H) administered for 6 weeks in adult rats. The possible roles of germ cell apoptosis and related genes expression were studied by techniques of TdT-mediated dUTP nick end-labeling (TUNEL), agarose gel electrophoresis of low-molecular-weight DNA, in situ hybridization and reverse transcription-polymerase chain reaction detection. Results showed that germ cell apoptosis and related genes expression were significantly induced after combined drug administration. The apoptosis index increased 3.86- and 9.65-fold in the 12-mg and 50-mg G+H-treated groups, respectively, as compared to the control group. DNA ladder formation on the agarose gel further validated the findings of TUNEL-stained apoptotic cells. The apoptosis-related genes fas mRNA expression levels increased 0.44- and 1.39-fold, bax mRNA 0.74- and 2.56-fold, caspase-3 mRNA 0.60- and 1.29-fold, and caspase-9 mRNA 2.50- and 4.08-fold, respectively, in the 12-mg and 50-mg G+H-treated groups vs. the control group. These results indicated that our drug regimen applied as a contraceptive could induce rat germ cell apoptosis. The apoptotic process involved fas system, bax and caspase family genes and the apoptotic extent and cell types were gossypol dose-dependent.


Assuntos
Apoptose/efeitos dos fármacos , Anticoncepcionais Masculinos/administração & dosagem , Etinilestradiol/administração & dosagem , Gossipol/administração & dosagem , Metiltestosterona/administração & dosagem , Espermatozoides/efeitos dos fármacos , Animais , Apoptose/genética , Caspases/genética , Anticoncepcionais Masculinos/efeitos adversos , Fragmentação do DNA , Gossipol/efeitos adversos , Hibridização In Situ , Marcação In Situ das Extremidades Cortadas , Masculino , Proteínas Proto-Oncogênicas c-bcl-2/genética , RNA Mensageiro/análise , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Espermátides/efeitos dos fármacos , Espermatócitos/efeitos dos fármacos , Proteína X Associada a bcl-2 , Receptor fas/genética
15.
J Dairy Sci ; 87(8): 2506-18, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15328274

RESUMO

Effects of varying amounts of gossypol from whole Upland cottonseed (WCS) and cottonseed meal (CSM) were evaluated in 40 midlactation Holstein cows. After 14 d of pretreatment, cows were assigned to 1 of the 5 treatments for 84 d: control (no gossypol), 931 mg/kg total gossypol (TG) and 850 mg/kg free gossypol (FG) from WCS (moderate TG and high FG); 924 mg/kg TG and 91 mg/kg FG from CSM (moderate TG and low FG), 945 mg/kg TG and 479 mg/kg FG with equal amounts of TG from WCS and CSM (moderate TG and FG), or 1894 mg/kg TG and 960 mg/kg FG with equal amounts of TG from WCS and CSM (high TG and FG). Concentrations of plasma gossypol (PG) and its isomers were directly proportional to FG intake. Concentrations of PG reached a plateau after 28 d on treatment, and they were highest in cows receiving a diet with high TG and FG. Erythrocyte fragility differed among treatments and increased with increasing FG intake. Plasma gossypol returned to negligible concentrations 28 d after withdrawal of cottonseed products from the high TG and FG diet. Serum vitamin A was similar among treatments, but vitamin E increased with increasing FG intake. Serum enzymes were generally unaffected by treatments, but urea N increased in diets higher in TG and FG. Intake of dry matter was higher for the diet high in TG and FG than for the control diet, but was similar for other treatments. Cows receiving the high TG and FG diet produced more milk and 3.5% fat-corrected milk, with no changes in milk composition. Feeding a diet containing 1894 mg/kg TG and 960 mg/kg FG for 84 d increased PG concentrations and erythrocyte fragility and resulted in minor changes in blood metabolites and enzymes, but no detrimental effect on lactation performance was observed. Indicators of liver, kidney, and muscle cell viability suggest that the higher amounts of gossypol consumed in this study had only minor effects on those tissues in lactating dairy cows.


Assuntos
Bovinos/sangue , Óleo de Sementes de Algodão/química , Dieta , Gossipol/administração & dosagem , Lactação/efeitos dos fármacos , Fenômenos Fisiológicos da Nutrição Animal , Animais , Temperatura Corporal , Bovinos/fisiologia , Enzimas/sangue , Feminino , Gossipol/sangue , Cinética , Leite/química , Fragilidade Osmótica/efeitos dos fármacos , Respiração , Vitamina A/sangue , Vitamina E/sangue
16.
J Dairy Sci ; 86(3): 892-905, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12703626

RESUMO

Objectives were to determine effects of altering gossypol intake by feeding whole linted Upland (WUP) or a 1:2 blend of WUP and cracked Pima (BUPCP) cottonseed on plasma gossypol (PG) concentrations, reproduction, and health of Holstein cows. Cows, 813, on three dairy farms were assigned to one of two diets starting at 13 +/- 11 d in milk for a 170-d experiment. Diets contained 717 and 951 mg of free gossypol/kg of dry matter from WUP and BUPCP, respectively. Concentrations of PG, as well as the proportion of total gossypol (TG) as the minus isomer were higher for cows fed BUPCP vs cows fed WUP. Conception rate at the first postpartum artificial insemination did not differ between treatments. However, cows consuming the higher gossypol diet had reduced subsequent conception rates and a lower pregnancy rate. Incidence of abortions increased in the higher gossypol diet, and cows that aborted or remained open had higher PG concentrations. Increasing PG concentrations resulted in reduced conception rates and extended days open. The probability of conception after the first artificial insemination declined at a decreasing rate as the plasma TG increased. Incidence of health disorders were unaffected by gossypol intake and PG concentrations. Similarly, gossypol intake and PG concentrations had no effect on culling or mortality. Six cows died in each diet, and none had postmortem signs compatible with gossypol toxicity. Consumption of a high gossypol diet for 170 d had no effect on health of lactating dairy cows, but it increased PG concentrations and impaired reproductive performance.


Assuntos
Bovinos/fisiologia , Óleo de Sementes de Algodão , Gossipol/administração & dosagem , Gossipol/sangue , Lactação , Reprodução/fisiologia , Aborto Animal/epidemiologia , Animais , Doenças dos Bovinos/epidemiologia , Doenças dos Bovinos/mortalidade , Dieta , Feminino , Nível de Saúde , Inseminação Artificial/veterinária , Coxeadura Animal/epidemiologia , Mastite Bovina/epidemiologia , Gravidez , Triglicerídeos/sangue
17.
J Anim Sci ; 80(9): 2485-92, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12350026

RESUMO

Superovulated Hereford-Angus crossbred heifers (average 397 kg BW) were used to test the effect of feeding cottonseed meal (gossypol) and vitamin E on embryo quality and ovarian characteristics. Twenty-four heifers were assigned randomly to four treatments with six heifers per treatment. Treatments were the following dietary supplements: 1) SBM (soybean meal + 30 IU vitamin E/kg of diet DM); 2) SBM+E (soybean meal + 4,000 IU vitamin E x animal(-1) x d(-1)); 3) CSM (cottonseed meal + 30 IU vitamin E/kg of diet DM); and 4) CSM+E (cottonseed meal + 4,000 IU vitamin E x animal(-1) x d(-1)). Supplements based on cottonseed meal provided 43.5 g of total gossypol/d (37% negative isomer (-) and 63% positive isomer (+)). Blood samples were collected at the start of the experiment and every 3 wk thereafter up to 12 wk. Plasma a-tocopherol (alpha-T) concentration was affected by treatments (P < 0.05). Heifers supplemented with cottonseed meal had greater (P < 0.05) alpha-T concentration in plasma than heifers supplemented with soybean meal at each concentration of vitamin E. Supplementation at 4,000 IU vitamin E x animal(-1) d(-1) increased (P < 0.05) the concentration of a-T in plasma. Weight gain, hemoglobin and hematocrit were not affected by treatment. Erythrocyte osmotic fragility (EOF) increased (P < 0.05) in cottonseed meal-fed animals; however, EOF was lowered (P < 0.05) with vitamin E supplementation. Heifers fed CSM and CSM+E supplements had greater (P < 0.01) concentrations of (-)-, (+)-, and total-gossypol in plasma, corpora lutea (CL), liver, and endometrium than heifers fed SBM and SBM+E supplements. Tissue alpha-T concentration increased with increased dietary supplemental vitamin E, particularly in great amounts in the CL. Because there was no adverse effect of gossypol on superovulation response or embryo development despite concentrations of gossypol in endometrium that are toxic to embryos, it is likely that systems exist in the reproductive tract to limit gossypol toxicity.


Assuntos
Bovinos/fisiologia , Embrião de Mamíferos/metabolismo , Gossipol/administração & dosagem , Vitamina E/administração & dosagem , Ração Animal , Animais , Bovinos/sangue , Bovinos/embriologia , Óleo de Sementes de Algodão , Relação Dose-Resposta a Droga , Endométrio/metabolismo , Endométrio/fisiologia , Eritrócitos/metabolismo , Feminino , Gossipol/efeitos adversos , Isomerismo , Fragilidade Osmótica , Gravidez , Distribuição Aleatória , Superovulação , alfa-Tocoferol/sangue
18.
J Dairy Sci ; 85(6): 1491-501, 2002 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12146481

RESUMO

Objectives were to determine the effects of feeding whole linted Upland (WUP) and cracked Pima cottonseed (BUPCP) to lactating cows on plasma gossypol concentrations and lactation performance. Holstein cows (n = 813) from three commercial dairies were assigned to one of two diets starting at 13+/-11 d in milk (DIM) for a 170-d experimental period. Cottonseed was included at 10% of the diet dry matter, and treatments consisted of replacing WUP with a 1:2 blend of BUPCP. Blood was collected from all cows at 61 and 91 DIM and from a subset of 56 cows on one dairy at 10, 33, 61, 91, 120, and 152 DIM. Intakes of free gossypol increased 32% in cows receiving the BUPCP diet, and concentrations of total gossypol (TG), as well as the proportion of TG as minus (-) isomer in plasma, were higher for cows fed BUPCP than WUP. Plasma TG increased linearly with increasing DIM, but cows fed the BUPCP, especially multiparous cows, had a higher increase in plasma TG over time. Yields of milk and milk components did not differ between the two treatments, although, yields of milk and milk components were greater in cows with higher plasma TG. Replacement of WUP cottonseed with BUPCP cottonseed increased plasma gossypol, but dry matter intake and yields of milk and milk components were not affected.


Assuntos
Bovinos/fisiologia , Óleo de Sementes de Algodão/classificação , Gossipol/administração & dosagem , Gossipol/sangue , Lactação/efeitos dos fármacos , Leite/metabolismo , Ração Animal , Animais , Bovinos/sangue , Bovinos/metabolismo , Ingestão de Energia , Feminino , Lactação/sangue , Lactação/fisiologia , Leite/química , Proteínas do Leite/análise , Valor Nutritivo , Distribuição Aleatória
19.
J Anim Physiol Anim Nutr (Berl) ; 86(7-8): 201-13, 2002 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15379906

RESUMO

Diets incorporating three different sources of extracted cottonseed meal (CM), soybean meal and an animal protein mixture were evaluated for juvenile rainbow trout. Fish averaging 0.96 g were divided into groups of 30; 3 groups per treatment, and each group was fed one of four diets for a 16-week period. Fish meal (FM) was replaced on a 25% protein basis by each of three different sources of CM from California (CA), Tennessee (TN), and Arkansas (AR), U.S.A. In the three CM-containing diets another 25% soybean meal protein and 50% animal protein mixture were also incorporated to completely replace FM protein. The results of growth rate and feed utilization showed that FM could be entirely replaced by a mixture of plant proteins (CM and soybean meal) and animal by-product proteins. Hematocrit levels were significantly lower in the group fed CM-containing diets than in the control. The findings suggest that CM can be used as a good protein source by the incorporation of at least 15% in diets (25% of fish meal protein replacement), and that the nutritive values of CM in juvenile trout can be different due to their different origin. Significantly higher concentrations of total gossypol were found in faeces of CM-TN (5.8 +/- 0.4 micromol/g) and CM-AR (5.6 +/- 0.6) groups than in that of CM-CA (3.7 +/- 0.4) group. It was documented that gossypol enantiomers, present in an equal proportion in diets, selectively accumulated in liver and bile, whereas equal proportions of (+)- and (-)-enantiomers were found in whole-body and faeces. Depending on CM source, fish can absorb approximately 35-50% of dietary gossypol, and the majority of the absorbed gossypol seemed to be excreted.


Assuntos
Ração Animal/análise , Fenômenos Fisiológicos da Nutrição Animal , Proteínas Alimentares/administração & dosagem , Gossipol/metabolismo , Oncorhynchus mykiss/crescimento & desenvolvimento , Animais , Aquicultura , Óleo de Sementes de Algodão , Proteínas Alimentares/metabolismo , Fezes/química , Gossipol/administração & dosagem , Gossipol/farmacocinética , Hematócrito , Absorção Intestinal , Valor Nutritivo , Oncorhynchus mykiss/metabolismo , Distribuição Aleatória , Glycine max
20.
J Dairy Sci ; 84(10): 2231-9, 2001 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11699455

RESUMO

Effects of feeding varying amounts of total gossypol from whole cottonseed and cottonseed meal were evaluated in 30 lactating Holstein cows. After a 14-d pretreatment period, cows were assigned for 42 d to one of five treatments: control (diet A); 1040 mg/kg of total gossypol, and 989 mg/kg of free gossypol from whole cottonseed (diet B); 900 mg/kg of total gossypol and 64 mg/kg of free gossypol from cottonseed meal (diet C); 960 mg/kg of total gossypol and 531 mg/kg of free gossypol with equal amounts of total gossypol from whole cottonseed and cottonseed meal (diet D); or 1922 mg/kg of total gossypol and 1050 mg/kg of free gossypol with equal amounts of total gossypol from whole cottonseed and cottonseed meal (diet E). Concentrations of plasma gossypol and its isomers were directly proportional to free gossypol intake. Plasma gossypol concentrations plateaued after 35 d on treatment, and they were highest in cows receiving diet E. At 42 d on treatment, erythrocyte fragility was higher in the cows receiving the diet E, but it did not differ among other treatments. Dry matter intakes were similar for all groups. Cows receiving diet E produced more milk and 3.5% fat-corrected milk, but milk protein content decreased. Feeding diets containing 1900 mg/kg of total gossypol and 1050 mg/kg of free gossypol for 42 d resulted in increased plasma gossypol concentrations and erythrocyte fragility, but no detrimental impact on lactation performance were observed.


Assuntos
Bovinos/fisiologia , Óleo de Sementes de Algodão/química , Gossipol/administração & dosagem , Lactação/efeitos dos fármacos , Leite/metabolismo , Animais , Bovinos/metabolismo , Gorduras/análise , Feminino , Gossipol/sangue , Lactação/metabolismo , Leite/química , Proteínas do Leite/análise , Fragilidade Osmótica
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