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1.
Cell Physiol Biochem ; 54(1): 53-70, 2020 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-31961100

RESUMO

BACKGROUND/AIMS: Genistein, a soy isoflavone, has been shown to have anti-cancer effects in various cancers including renal cancer. Long non-coding RNA, HOX transcript antisense RNA (HOTAIR), is involved in cancer progression and metastasis, such as renal cancer. Our aim was to investigate the effects of genistein on HOTAIR chromatin remodeling functions. METHODS: We used MTS assays and Transwell migration assays to study the effects of genistein on cell proliferation and migration respectively in human renal cell carcinoma (RCC) cell lines. We used Western blots to analyze SNAIL and ZO-1 expression. We performed chromatin immunoprecipitation (ChIP) assays to study recruitment of the polycomb repressive complex 2 (PRC2) to the ZO-1 promoter. We performed RNA immunoprecipitation (RIP) assays to study interaction between HOTAIR and PRC2, SMARCB1 or ARID1A. We also performed transfection experiments to overexpress EED, HOTAIR and knockdown SMARCB1. RESULTS: Genistein reduced cell proliferation and migration of human renal cell carcinoma cell lines. ChIP assays indicated that genistein reduces recruitment of the PRC2 to the ZO-1 promoter and increased its expression. RIP assays showed that genistein inhibits HOTAIR interaction with PRC2, leading to tumor suppression. Immunoprecipitation also revealed that genistein reduced EED levels in PRC2, suggesting that decreased EED levels suppress HOTAIR interaction with PRC2. EED overexpression in the presence of genistein restored PRC2 interaction with HOTAIR and reduced ZO-1 transcription, suggesting genistein activates ZO-1 by inhibiting HOTAIR/PRC2 functions. RIP assays also showed that HOTAIR interacts with SMARCB1 and ARID1A, subunits of the human SWI/SNF chromatin remodeling complex and genistein reduces this interaction. Combination of HOTAIR overexpression and SMARCB1 knockdown in the presence of genistein revealed that genistein inhibits SNAIL transcription via the HOTAIR/SMARCB1 pathway. CONCLUSION: Genistein suppresses EED levels in PRC2 and inhibits HOTAIR/PRC2 interaction. Genistein suppresses HOTAIR/PRC2 recruitment to the ZO-1 promoter and enhances ZO-1 transcription. Genistein also inhibits SNAIL transcription via reducing HOTAIR/SMARCB1 interaction. We demonstrate that the reduction of HOTAIR interaction with chromatin remodeling factors by genistein represses HOTAIR/chromatin remodeling pathways to suppress RCC malignancy.


Assuntos
Anticarcinógenos/farmacologia , Montagem e Desmontagem da Cromatina/efeitos dos fármacos , Genisteína/farmacologia , Neoplasias Renais/tratamento farmacológico , RNA Longo não Codificante/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Renais/genética , Invasividade Neoplásica/genética , Invasividade Neoplásica/prevenção & controle
2.
Life Sci ; 241: 117061, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31794774

RESUMO

The consumption of cruciferous vegetables rich in isothiocyanates has long been associated with a reduced risk of various types of cancer. 4-(methylthio)butyl isothiocyanate also called erucin is an isothiocyanate present in appreciable quantity in the seeds of Eruca sativa Mill. plant. Although the literature has revealed its protective effects via inducing phase II enzymes and inhibiting carcinogen activating phase I enzymes, recent studies also suggest that, it inhibits the proliferation of cancer cells by altering the telomerase activity, dynamics of microtubules, expression of histone deacetylases, and other molecular pathways. With this in mind, the emphasis has been made to review the molecular targets involved in cancer prevention by 4-(methylthio)butyl isothiocyanate.


Assuntos
Anticarcinógenos/farmacologia , Antineoplásicos/farmacologia , Isotiocianatos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Humanos , Telomerase/metabolismo , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
3.
J Biochem Mol Toxicol ; 34(2): e22428, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31860765

RESUMO

The aim of this study is to confirm the toxic effect of phenylethyl isothiocyanate (PEITC) on porcine kidney cells (PK-15) and explore the effect of oxidative damage mediated by reactive oxygen species (ROS) induced by PEITC in PK-15 cells. Porcine kidney cell line (PK-15) was treated with PEITC (2, 5, and 10 µM) for 24 hours, and the oxidative damage mediated by PEITC through ROS was investigated. The survival rate of PK-15 cells decreased in a dose-dependent manner after the treatment of PEITC in a dose-dependent manner. A high concentration of PEITC (10 µM) can change cell morphology, increase the content of malondialdehyde, ROS, and lactate dehydrogenase, and decrease the activity of SOD, CAT, GSH-PX, and GSH. PEITC has a toxic effect on PK-15 cells by inducing oxidative stress in PK-15 cells through the generation of ROS.


Assuntos
Anticarcinógenos/efeitos adversos , Anticarcinógenos/farmacologia , Isotiocianatos/efeitos adversos , Isotiocianatos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Animais , Brassica napus/química , Catalase/metabolismo , Linhagem Celular , Membrana Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , L-Lactato Desidrogenase/metabolismo , Malondialdeído/metabolismo , Superóxido Dismutase/metabolismo , Suínos
4.
Environ Toxicol ; 35(1): 47-54, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31587482

RESUMO

Benzyl isothiocyanate (BITC), a bioactive natural product present in cruciferous vegetables, has been proved to prevent cancer progression through various mechanisms. In our previous report, we proved that BITC exhibits antitumor effects in bladder cancer by suppressing IGF1R, FGFR3, and mTOR, which is mediated by miR-99a expression. In this study, we identified the signal pathway involved in regulating miR-99a expression after BITC exposure in bladder cancer. Treatment with different BITC concentrations resulted in induction of miR-99a expression in bladder cancer cell lines. Activation of extracellular signal-regulated protein kinase (ERK) and c-jun N-terminal kinase was observed in bladder cancer after BITC treatment for 24 hours. Interestingly, by using a chemical inhibitor of candidate pathways, we found that only the ERK signal pathway is required for miR-99a expression. Furthermore, we evaluated the transcription factor that may contribute to miR-99a expression in response to BITC treatment. The results indicated that c-Jun/AP-1 was activated after BITC treatment. Moreover, we confirmed c-Jun/AP-1 activation through immunofluorescence and the luciferase reporter assay. The results showed that BITC treatment markedly improved nuclear translocation of c-Jun/AP-1 and luciferase activity dose dependently. Finally, pretreatment with the ERK inhibitor U0126 diminished c-Jun phosphorylation and transcriptional activation, suggesting that BITC elicits ERK/c-Jun signal transduction, which is responsible for miR-99a expression in bladder cancer. The present work identifies the mechanism involved in upregulation miR-99a after BITC treatment, which provides an explanation for BITC biological function in our previous work.


Assuntos
Anticarcinógenos/farmacologia , Isotiocianatos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , MicroRNAs/genética , Fator de Transcrição AP-1/metabolismo , Neoplasias da Bexiga Urinária/prevenção & controle , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Fosforilação , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Regulação para Cima , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia
5.
PLoS One ; 14(12): e0226639, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31881053

RESUMO

Raloxifene is commonly used for breast cancer protection. The low bioavailability of raloxifene (2%) is the result of its low solubility and intestinal glucuronidation. The nano-lipid carriers are characterized by small particle size, biocompatibility, and sustainable properties that improve cellular uptake of the loaded drug. The aim of this study was the improvement of raloxifene bioavailability by enhancing its solubility and cellular penetration through formulation of D-α-tocopheryl polyethylene glycol 1000 succinate based transferosomes and augmenting their effect with the cationic cell-penetrating peptide transactivator of transcription of the human immunodeficiency virus. Particle size, zeta potential, and transmission electron microscope investigation of the formed nanocarriers were carried out. Ex vivo raloxifene permeation through rat skin and cell viability studies was investigated. The results of D-α-tocopheryl polyethylene glycol 1000 succinate- transactivator of transcription of the human immunodeficiency virus transferosomes showed an average vesicle size of 96.05 nm with positively charged vesicles 39.4 mV of zeta potential value. The results revealed significant (p < 0.05) enhancement of raloxifene permeation from raloxifene transferosomes- loaded film when compared with raw raloxifene film. IC50 results showed significant improvement of formulated raloxifene cytotoxicity by 1.42-fold in comparison with raw raloxifene against MCF-7 cell lines. The developed raloxifene-transferosomes are considered promising nano-lipid carriers for the enhancement delivery of raloxifene.


Assuntos
Portadores de Fármacos/metabolismo , Cloridrato de Raloxifeno/administração & dosagem , Moduladores Seletivos de Receptor Estrogênico/administração & dosagem , Vitamina E/metabolismo , Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo , Administração Cutânea , Animais , Anticarcinógenos/administração & dosagem , Anticarcinógenos/farmacocinética , Anticarcinógenos/farmacologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/prevenção & controle , Feminino , Humanos , Células MCF-7 , Cloridrato de Raloxifeno/farmacocinética , Cloridrato de Raloxifeno/farmacologia , Ratos Wistar , Moduladores Seletivos de Receptor Estrogênico/farmacocinética , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Absorção Cutânea
6.
Zhonghua Yu Fang Yi Xue Za Zhi ; 53(11): 1098-1103, 2019 Nov 06.
Artigo em Chinês | MEDLINE | ID: mdl-31683394

RESUMO

Objective: To describe the status of non-steroidal anti-inflammatory drugs (NSAIDs) use in areas with a high incidence of upper gastrointestinal cancer in China. Methods: This study was based on the National Key Research and Development Program of "National Precision Medicine Cohort of Esophageal Cancer" and "Study on Identification and Prevention of High-risk Populations of Gastrointestinal Malignancies (Esophageal cancer, Gastric cancer and Colorectal cancer)" . From January 2017 to August 2018, 212 villages or communities with a high incidence of esophageal cancer or gastric cancer were selected from 12 regions in 6 provinces. A total of 35 910 residents aged between 40 and 69 years old who met the inclusion criteria and signed the informed consent were investigated and enrolled in this study. The use of NSAIDs, demographic characteristics, health-related habits, height, weight, and blood pressure were collected by the questionnaire and physical examination. The status of main NSAIDs (aspirin, acetaminophen and ibuprofen) use with the difference varying in genders, age groups and regions were analyzed by using χ(2) test and Cochran-Armitage trend analysis method. Results: Of 35 910 subjects, the mean age was (54.6±7.1) years old and males accounted for 43.42% (15 591). The overall prevalence of NSAIDs intake was 4.56% (1 638), but it significantly varied in different provinces (P<0.001). The overall prevalence of NSAIDs intake was 4.87% (1 750) in females, which was significantly higher than that in males 4.24% (1 524) (P<0.001). The prevalence of NSAIDs intake increased with age (P for trend <0.001). As the frequency of NSAIDs intake increased, the incidence of gastrointestinal symptoms, gastrointestinal ulcers and black stools increased (P for trend <0.05 for all). Conclusion: The use of NSAIDs is prevalent in some areas with a high incidence of upper gastrointestinal cancer in China. The increased use of NSAIDs may lead to more adverse effects related to the gastrointestinal tract.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Anticarcinógenos/efeitos adversos , Aspirina/efeitos adversos , Neoplasias Gastrointestinais/epidemiologia , Ibuprofeno/efeitos adversos , Adulto , Idoso , Anti-Inflamatórios não Esteroides/farmacologia , Anticarcinógenos/farmacologia , Aspirina/farmacologia , China/epidemiologia , Estudos Transversais , Feminino , Neoplasias Gastrointestinais/induzido quimicamente , Neoplasias Gastrointestinais/etnologia , Humanos , Ibuprofeno/farmacologia , Incidência , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários
7.
Artigo em Inglês | MEDLINE | ID: mdl-31591291

RESUMO

(1) Background: In recent decades, the prevalence of obesity has grown rapidly worldwide, thus causing many diseases, including male hypogonadism. Sulforaphane (SFN), an isothiocyanate compound, has been reported to protect the reproductive system. This research investigated the protective effect of SFN against obesity-induced impairment in the male reproductive system and explored the potential mechanism involved in mice. (2) Methods: One hundred thirty mice were divided into 5 groups (Control, DIO (diet-induced obesity), DIO + SFN 5 mg/kg, DIO + SFN 10 mg/kg, and DIO + SFN 20 mg/kg). The effects of SFN on the male reproductive system were determined based on the sperm count and motility, relative testes and epididymis weights, hormone levels, and pathological analyses. Oxidative stress was determined by measuring malondialdehyde (MDA), total antioxidant capacity (T-AOC), superoxide dismutase (SOD), glutathione (GSH), H2O2, catalase (CAT), and glutathione peroxidase (GSH-PX) levels. Protein expression of nuclear factor erythroid-2 related factor 2 (Nrf2), Kelch-like ECH-associated protein-1 (Keap1), Microtubule-associated protein light chain 3 (LC3), Beclin1, and P62 were determined by western blotting. (3) Results: High-fat diet (HFD)-induced obesity significantly decreased relative testes and epididymis weights, sperm count and motility, and testosterone levels but increased leptin and estradiol levels. SFN supplementation ameliorated these effects. Additionally, SFN administration inhibited the obesity-induced MDA accumulation and increased the SOD level. Western blot indicated that SFN had an important role in the downregulation of Keap1. Moreover, SFN treatment attenuated obesity-induced autophagy, as detected by LC3 and Beclin1. (4) Conclusions: SFN ameliorated the reproductive toxicity associated with obesity by inhibiting oxidative stress mediated by the nuclear factor erythroid-2 related factor 2/ antioxidant response element (Nrf2/ARE) signaling pathway and recovery of normal autophagy.


Assuntos
Anticarcinógenos/farmacologia , Autofagia/efeitos dos fármacos , Genitália Masculina/fisiopatologia , Isotiocianatos/farmacologia , Obesidade/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Masculino , Camundongos , Substâncias Protetoras/farmacologia , Transdução de Sinais/efeitos dos fármacos
8.
Int J Mol Sci ; 20(20)2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31600949

RESUMO

The use of synthetic, natural, or biological agents to minimize the occurrence of cancer in healthy individuals is defined as cancer chemoprevention. Chemopreventive agents inhibit the development of cancer either by impeding DNA damage, which leads to malignancy or by reversing or blocking the division of premalignant cells with DNA damage. The benefit of this approach has been demonstrated in clinical trials of breast, prostate, and colon cancer. The continuous increase in cancer cases, failure of conventional chemotherapies to control cancer, and excessive toxicity of chemotherapies clearly demand an alternative approach. The first trial to show benefit of chemoprevention was undertaken in breast cancer patients with the use of tamoxifen, which demonstrated a significant decrease in invasive breast cancer. The success of using chemopreventive agents for protecting the high risk populations from cancer indicates that the strategy is rational and promising. Dietary components such as capsaicin, cucurbitacin B, isoflavones, catechins, lycopenes, benzyl isothiocyanate, phenethyl isothiocyanate, and piperlongumine have demonstrated inhibitory effects on cancer cells indicating that they may serve as chemopreventive agents. In this review, we have addressed the mechanism of chemopreventive and anticancer effects of several natural agents.


Assuntos
Anticarcinógenos/química , Anticarcinógenos/farmacologia , Quimioprevenção , Neoplasias/prevenção & controle , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Animais , Humanos , Neoplasias/etiologia , Relação Estrutura-Atividade
9.
BMC Cancer ; 19(1): 864, 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31470802

RESUMO

BACKGROUND: Bronchial carcinoids are neuroendocrine tumors that present as typical (TC) and atypical (AC) variants, the latter being more aggressive, invasive and metastatic. Studies of tumor initiating cell (TIC) biology in bronchial carcinoids has been hindered by the lack of appropriate in-vitro and xenograft models representing the bronchial carcinoid phenotype and behavior. METHODS: Bronchial carcinoid cell lines (H727, TC and H720, AC) were cultured in serum-free growth factor supplemented medium to form 3D spheroids and serially passaged up to the 3rd generation permitting expansion of the TIC population as verified by expression of stemness markers, clonogenicity in-vitro and tumorigenicity in both subcutaneous and orthotopic (lung) models. Acetazolamide (AZ), sulforaphane (SFN) and the AZ + SFN combination were evaluated for targeting TIC in bronchial carcinoids. RESULTS: Data demonstrate that bronchial carcinoid cell line 3rd generation spheroid cells show increased drug resistance, clonogenicity, and tumorigenic potential compared with the parental cells, suggesting selection and expansion of a TIC fraction. Gene expression and immunolabeling studies demonstrated that the TIC expressed stemness factors Oct-4, Sox-2 and Nanog. In a lung orthotopic model bronchial carcinoid, cell line derived spheroids, and patient tumor derived 3rd generation spheroids when supported by a stroma, showed robust tumor formation. SFN and especially the AZ + SFN combination were effective in inhibiting tumor cell growth, spheroid formation and in reducing tumor formation in immunocompromised mice. CONCLUSIONS: Human bronchial carcinoid tumor cells serially passaged as spheroids contain a higher fraction of TIC exhibiting a stemness phenotype. This TIC population can be effectively targeted by the combination of AZ + SFN. Our work portends clinical relevance and supports the therapeutic use of the novel AZ+ SFN combination that may target the TIC population of bronchial carcinoids.


Assuntos
Acetazolamida/administração & dosagem , Anticarcinógenos/administração & dosagem , Neoplasias Brônquicas/tratamento farmacológico , Tumor Carcinoide/tratamento farmacológico , Isotiocianatos/administração & dosagem , Células-Tronco Neoplásicas/efeitos dos fármacos , Acetazolamida/farmacologia , Animais , Anticarcinógenos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Brônquicas/genética , Neoplasias Brônquicas/metabolismo , Tumor Carcinoide/genética , Tumor Carcinoide/metabolismo , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Isotiocianatos/farmacologia , Camundongos , Proteína Homeobox Nanog/genética , Proteína Homeobox Nanog/metabolismo , Células-Tronco Neoplásicas/citologia , Células-Tronco Neoplásicas/metabolismo , Fator 3 de Transcrição de Octâmero/genética , Fator 3 de Transcrição de Octâmero/metabolismo , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição SOXB1/metabolismo , Esferoides Celulares/citologia , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
10.
BMC Complement Altern Med ; 19(1): 238, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31481122

RESUMO

BACKGROUND: Annonacin, an annonaceous acetogenin isolated from Annona muricata has been reported to be strongly cytotoxic against various cell lines, in vitro. Nevertheless, its effect against in vivo tumor promoting activity has not been reported yet. Therefore, this study was aimed to investigate antitumor-promoting activity of annonacin via in vivo two-stage mouse skin tumorigenesis model and its molecular pathways involved. METHODS: Mice were initiated with single dose of 7,12-dimethylbenz[α]anthracene (DMBA) (390 nmol/100 µL) followed by, in subsequent week, repeated promotion (twice weekly; 22 weeks) with 12-O-tetradecanoylphorbol-13-acetate (TPA) (1.7 nmol/100 µL). Annonacin (85 nM) and curcumin (10 mg/kg; reference) were, respectively, applied topically to DMBA/TPA-induced mice 30 min before each TPA application for 22 weeks. Upon termination, histopathological examination of skin, liver and kidney as well as genes and proteins expression analysis were conducted to elucidate the potential mechanism of annonacin. RESULTS: With comparison to the carcinogen control, Annonacin significantly increased the tumor latency period and reduced the tumor incidence, tumor burden and tumor volume, respectively. In addition, it also suppressed tumorigenesis manifested by significant reduction of hyperkeratosis, dermal papillae and number of keratin pearls on skin tissues. Annonacin also appeared to be non-toxic to liver and kidney. Significant modulation of both AKT, ERK, mTOR, p38, PTEN and Src genes and proteins were also observed in annonacin-targeted signaling pathway(s) against tumorigenesis. CONCLUSIONS: Collectively, results of this study indicate that annonacin is a potential therapeutic compound targeting tumor promoting stage in skin tumorigenesis by modulating multiple gene and protein in cancer signaling pathways without apparent toxicity.


Assuntos
Anticarcinógenos/farmacologia , Carcinogênese/efeitos dos fármacos , Furanos/farmacologia , Lactonas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Neoplasias Cutâneas , 9,10-Dimetil-1,2-benzantraceno/toxicidade , Animais , Carcinógenos/toxicidade , Feminino , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Pele/efeitos dos fármacos , Pele/patologia , Neoplasias Cutâneas/induzido quimicamente , Neoplasias Cutâneas/metabolismo , Acetato de Tetradecanoilforbol/toxicidade
11.
J Vet Med Sci ; 81(10): 1424-1430, 2019 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-31527340

RESUMO

Osteosarcoma (OSA) is the most common bone tumor in dogs. Protein phosphatase 2A (PP2A), an evolutionary conserved serine/threonine protein phosphatase, is a crucial tumor suppressor. SET is a PP2A inhibitory protein that directly interacts with PP2A and suppresses its phosphatase activity. SET has been reported as a contributor of wide range of human and dog tumor malignancies. However, the role of SET in canine OSA (cOSA) remains unknown. In this study, we investigated the role of SET in cOSA by using 2 cOSA cell lines: POS (primary origin) and HM-POS (metastatic origin). Knockdown (KD) of SET expression was noted to slightly suppress POS cell proliferation only. Furthermore, SET KD effectively suppressed colony formation ability of both POS and HM-POS cells. SET KD was observed to repress ERK1/2, mTOR, E2F1, and NF-κB signaling in HM-POS cells, whereas it inhibited only ERK1/2 signaling in POS. Further, it was observed that SET-targeting drug, FTY720, exerted anti-cancer effects in both POS and HM-POS cells. Moreover, the drug also enhanced the anti-cancer effect of cisplatin. The data suggested that a combination therapy, based on SET targeting drugs and cisplatin, could be a potent strategy for cOSA.


Assuntos
Neoplasias Ósseas/veterinária , Inibidores de Calcineurina/farmacologia , Osteossarcoma/veterinária , Proteína Fosfatase 2/metabolismo , Animais , Anticarcinógenos/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Inibidores de Calcineurina/uso terapêutico , Linhagem Celular Tumoral , Cisplatino/farmacologia , Cães , Sinergismo Farmacológico , Cloridrato de Fingolimode/farmacologia , Osteossarcoma/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos
12.
Biomed Pharmacother ; 118: 109144, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31545234

RESUMO

Gastric cancer is one of the most common cancers leading to tumor-related deaths worldwide. Chicoric acid (CA) exhibits a variety of protective effects in different diseases. However, its role in regulating tumor progression has not been reported. Autophagy, as a conserved catabolic process, sustains cellular homoeostasis responding to stress to modulate cell fate. In the study, the effects of CA on gastric cancer were investigated. The results indicated that CA treatment markedly reduced the cell viability and induced apoptosis in gastric cancer cells, and prevented tumor growth in an established xenograft gastric cancer model. Furthermore, CA exposure significantly induced autophagy both in gastric cancer cells and tumor samples, as evidenced by the up-regulated expression of LC3II. Moreover, phosphorylated AMP-activated protein kinase (AMPK) and p70S6 kinase (p70s6k) expression were obviously promoted by CA in vitro and in vivo. Importantly, blocking AMPK activation abrogated CA-induced expression of LC3II in gastric cancer cells. In addition, endoplasmic reticulum (ER) stress in tumor samples or cells was markedly induced by CA treatment through promoting the expression of associated signals such as Parkin, protein kinase RNA-like ER kinase (PERK), activating transcription factors 4 (ATF4) and ATF6. Importantly, these effects were abolished by the inhibition of AMPK signaling. Collectively, our findings indicated that CA prevents human gastric cancer progression by inducing autophagy partly through the activation of AMPK, and represents an effective therapeutic strategy against gastric cancer development.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Anticarcinógenos/farmacologia , Autofagia/efeitos dos fármacos , Ácidos Cafeicos/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Neoplasias Gástricas/prevenção & controle , Succinatos/farmacologia , Animais , Anticarcinógenos/sangue , Ácidos Cafeicos/sangue , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Ratos , Ratos Sprague-Dawley , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Succinatos/sangue
13.
Toxicol Mech Methods ; 29(9): 710-722, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31364915

RESUMO

Background: Fennel (Foeniculum vulgare) and clove (Syzygium aromaticum) oils are known for their various biological effects, including anticancer properties. Objective: To investigate the anticancer effect of combined fennel and clove oil treatment on Caco-2 cells and normal human lymphocytes (NHL). Methods: GC-MS, in vitro cytotoxicity, morphological, apoptosis-related marker, and flow cytometric cell cycle distribution analyses were conducted. Results: Seventeen volatile compounds were identified in fennel oil, including trans-anethole (68.3%) and (+)-fenchone (8.1%). In clove oil, 22 compounds, including eugenol (71.4%) and caryophyllene (8.7%), were identified. IC50 of the fennel, clove, and oil mixture were 300 ± 5.0, 150 ± 4.0, and 73 ± 2.5 µg/mL, respectively with combination index (CI) < 1.0. Mechanistic anticancer properties were investigated using 30, 45, and 60 µg/mL oil mixture. Analysis of apoptotic morphology, flow cytometric cell cycle distribution, and apoptosis-related markers, such as Bcl-2 and Ki-67, confirmed cell cycle arrest and apoptosis induction in Caco-2 cells by the fennel and clove oil combination. Moreover, the oil mixture did not exert significant (p < 0.01) toxicity on NHL in vitro. Conclusion: The oil mixture exerted selective cytotoxicity towards Caco-2 cells through cell cycle arrest and apoptosis, which may occur through synergistic effects between fennel and clove oil active ingredients.


Assuntos
Anticarcinógenos/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Óleo de Cravo/farmacologia , Foeniculum/química , Óleos Voláteis/farmacologia , Syzygium/química , Anticarcinógenos/isolamento & purificação , Células CACO-2 , Óleo de Cravo/isolamento & purificação , Sinergismo Farmacológico , Humanos , Óleos Voláteis/isolamento & purificação
14.
Int J Mol Sci ; 20(15)2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31374832

RESUMO

Chronic inflammation can lead to tumour initiation and progression. Vitamin B complex has the ability to regulate the immune response and, therefore, inflammation but many of the mechanistic and molecular processes involved in this regulation are still not fully understood. This study sought to determine some of these processes by studying the effects of vitamin B2 (riboflavin) B6 (pyridoxine) and B9 (folic acid) on un-differentiated pro-monocytic lymphoma cells in regard to their ability to alter the proliferation, migration, apoptosis, cytokines and expression levels of programmed death ligand 1. We show that vitamin B2, B6 and B9, on pro-monocytic lymphoma cells exerted an anti-tumorigenic effect. This data could form the basis for future studies in using vitamin B supplementation to reduce cancer cell growth in vivo.


Assuntos
Anticarcinógenos/farmacologia , Ácido Fólico/farmacologia , Linfoma/tratamento farmacológico , Riboflavina/farmacologia , Vitamina B 6/farmacologia , Adulto , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Linfoma/patologia , Masculino
15.
Molecules ; 24(16)2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31394732

RESUMO

Chemoprevention by ingested substituents is the process through which nutraceuticals and/or their bioactive components antagonize carcinogenesis. Carcinogenesis is the course of action whereby a normal cell is transformed into a neoplastic cell. This latter action involves several steps, starting with initiation and followed by promotion and progression. Driving these stages is continued oxidative stress and inflammation, which in turn, causes a myriad of aberrant gene expressions and mutations within the transforming cell population and abnormal gene expressions by the cells within the surrounding lesion. Chemoprevention of cancer with bioreactive foods or their extracted/purified components occurs primarily via normalizing these inappropriate gene activities. Various foods/agents have been shown to affect different gene expressions. In this review, we discuss how the chemoprevention activities of gingers antagonize cancer development.


Assuntos
Anticarcinógenos/química , Anticarcinógenos/farmacologia , Gengibre/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Animais , Quimioprevenção , Humanos , Relação Estrutura-Atividade
16.
Curr Pharm Des ; 25(11): 1210-1235, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31465281

RESUMO

BACKGROUND: Algal polysaccharide and oligosaccharide derivatives have been shown to possess a variety of therapeutic potentials and drug delivery applications. Algal polysaccharides contain sulfated sugar monomers derived from seaweed including brown, red, and green microalgae. Here, in this review, the recent progress of algal polysaccharides' therapeutic applications as anticancer agents, as well as underlying cellular and molecular mechanisms was investigated. Moreover, recent progress in the structural chemistry of important polysaccharides with anticancer activities were illustrated. METHODS: Electronic databases including "Scopus", "PubMed", and "Cochrane library" were searched using the keywords "cancer", or "tumor", or "malignancy" in title/abstract, along with "algae", or "algal" in the whole text until July 2018. Only English language papers were included. RESULTS: The most common polysaccharides involved in cancer management were sulfated polysaccharides, Fucoidans, Carageenans, and Ulvan from different species of algae that have been recognized in vitro and in vivo. The underlying anticancer mechanisms of algal polysaccharides included induction of apoptosis, cell cycle arrest, modulation of transduction signaling pathways, suppression of migration and angiogenesis, as well as activation of immune responses and antioxidant system. VEGF/VEGFR2, TGFR/Smad/Snail, TLR4/ROS/ER, CXCL12/ CXCR4, TGFR/Smad7/Smurf2, PI3K/AKT/mTOR, PBK/TOPK, and ß-catenin/Wnt are among the main cellular signaling pathways which have a key role in the preventive and therapeutic effects of algal polysaccharides against oncogenesis. CONCLUSION: Algal polysaccharides play a crucial role in the management of cancer and may be considered the next frontier in pharmaceutical research. Further well-designed clinical trials are mandatory to evaluate the efficacy and safety of algal polysaccharides in patients with cancer.


Assuntos
Anticarcinógenos/farmacologia , Neoplasias/prevenção & controle , Polissacarídeos/farmacologia , Alga Marinha/química , Humanos , Polissacarídeos/química , Sulfatos/química
17.
Artif Cells Nanomed Biotechnol ; 47(1): 3577-3584, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31456423

RESUMO

Gold nanoparticles (AuNPs) is the most excellent anticancer theranostic nanoparticles synthesized through efficient, simple and green synthesis method using extracts of Trichosanthes kirilowii, extensively characterized by UV-spectroscopy, FT-IR and TEM techniques. The AuNPs, synthesized by means of T. kirilowii extracts identified that nanoparticles were ∼50 nm in size, which is an admirable nano dimension attained by green synthesis. In agreement with the outcome of microscopic cellular morphological observations, MTT assay showed effective, selective, anticarcinogenic effect of AuNPs on HCT-116 cells in a dose-dependent manner. The AuNPs significantly enhance ROS generation, cause mitochondrial membrane damage and induce morphological changes using AO/EtBr staining assay. Furthermore, AuNPs treatment induces G0/G1 phase cell-cycle arrest in HCT-116 cells. Also, AuNPs treatment activates caspase expression and downregulates the anti-apoptotic expression in HCT-116 cells. Our results point out that the phytoconsituents isolated from T. kirilowii can act as appropriate reducing and stabilizing agents in the properties of AuNPs; hereby, it leads to the green synthesis of an anti-carcinogenic agent with highly efficient potential for cancer treatment.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias do Colo/patologia , Ouro/química , Ouro/farmacologia , Nanopartículas Metálicas , Trichosanthes/metabolismo , Anticarcinógenos/química , Anticarcinógenos/metabolismo , Anticarcinógenos/farmacologia , Ciclo Celular/efeitos dos fármacos , Ouro/metabolismo , Células HCT116 , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos
18.
J Exp Clin Cancer Res ; 38(1): 307, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31307507

RESUMO

BACKGROUND: We reported previously that phenethyl isothiocyanate (PEITC), a dietary compound, can reactivate p53R175H mutant in vitro and in SK-BR-3 (p53R175H) breast xenograft model resulting in tumor inhibition. Because of the diversity of human cancers with p53 mutations, these findings raise important questions whether this mechanism operates in different cancer types with same or different p53 mutations. In this study, we investigated whether PEITC recuses mutant p53 in prostate cancer cells harboring different types of p53 mutants, structural and contact, in vitro and in vivo. METHODS: Cell proliferation, cell apoptosis and cell cycle arrest assays were performed to examine the effects of PEITC on prostate cancer cell lines with p53 mutation(s), wild-type p53, p53 null or normal prostate cells in vitro. Western blot analysis was used to monitor the expression levels of p53 protein, activation of ATM and upregulation of canonical p53 targets. Immunoprecipitation, subcellular protein fraction and qRT-PCR was performed to determine change in conformation and restoration of transactivation functions/ inhibition of gain-of-function (GOF) activities to p53 mutant(s). Mice xenograft models were established to evaluate the antitumor efficacy of PEITC and PEITC-induced reactivation of p53 mutant(s) in vivo. Immunohistochemistry of xenograft tumor tissues was performed to determine effects of PEITC on expression of Ki67 and mutant p53 in vivo. RESULTS: We demonstrated that PEITC inhibits the growth of prostate cancer cells with different "hotspot" p53 mutations (structural and contact), however, preferentially towards structural mutants. PEITC inhibits proliferation and induces apoptosis by rescuing mutant p53 in p53R248W contact (VCaP) and p53R175H structural (LAPC-4) mutant cells with differential potency. We further showed that PEITC inhibits the growth of DU145 cells that co-express p53P223L (structural) and p53V274F (contact) mutants by targeting p53P223L mutant selectively, but not p53V274F. The mutant p53 restored by PEITC induces apoptosis in DU145 cells by activating canonical p53 targets, delaying cells in G1 phase and phosphorylating ATM. Importantly, PEITC reactivated p53R175H and p53P223L/V274F mutants in LAPC-4 and DU145 prostate xenograft models, respectively, resulting in significant tumor inhibition. CONCLUSION: Our studies provide the first evidence that PEITC's anti-cancer activity is cancer cell type-independent, but p53 mutant-type dependent.


Assuntos
Anticarcinógenos/administração & dosagem , Isotiocianatos/administração & dosagem , Neoplasias da Próstata/tratamento farmacológico , Proteína Supressora de Tumor p53/genética , Animais , Anticarcinógenos/farmacologia , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Isotiocianatos/farmacologia , Masculino , Camundongos , Mutação , Fosforilação , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Phytomedicine ; 63: 153011, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31301538

RESUMO

BACKGROUND: Ilexgenin A (IA), the main bioactive compound from Ilex hainanensis Merr., has significant hypolipidemic activities. However, the effects of IA on colitis-associated colorectal cancer (CRC) and its mechanisms are still unknown. PURPOSE: The study was designed to evaluate the effect of IA on CRC and explore its underlying mechanisms. STUDY DESIGN: The effect of IA on colitis related CRC were evaluated in azoxymethane (AOM)/dextran sulfate sodium (DSS) mice and the underlying mechanisms were revealed by metabolomics, which were further validated in vivo and in vitro. METHODS: The Balb/c mice were treated with AOM/DSS to induce CRC model and fed with normal diet with or without 0.02% IA. After the experimental period, samples of plasma were collected and analyzed by ultra-high-performance liquid chromatography/quadrupole time off light mass spectrometry (UHPLC-Q-TOF). Multivariate statistical tools were used to identify the changes of serum metabolites associated with CRC and responses to IA treatment. HT 29 and HCT 116 cells were stimulated by palmitate (PA) and cultured under hypoxia. Western blot, Q-PCR, and Immunofluorescence staining were performed to confirm the molecular pathway in vivo and in vitro. RESULTS: Our results showed IA significantly inhibited the inflammatory colitis symptoms such as disease activity index score, shortening of colon tissues and the increase of inflammatory cytokines. In metabolomic study, 31 potential metabolites associated with CRC were identified and 24 of them were reversed by IA treatment. Most of biomarkers were associated with arachidonic acid metabolism, glycerophospholipid catabolism, and phospholipid metabolism, suggesting lipid metabolism might be involved in the beneficial effect of IA on CRC. Furthermore, we also found IA could decrease the expressions of SREBP-1 and its target gene in the colon tissues of AOM/DSS mice. It could down-regulate the triglyceride (TG) content and the expressions of HIF1α, SREBP-1, FASN, and ACC in HT 29 and HCT 116 cells. The inhibitory effect of IA on SREBP-1 was also attenuated by desferrioxamine (DFX), suggesting HIF1α is involved in the regulation of IA on SREBP-1. CONCLUSION: IA prevents early colonic carcinogenesis in AOM/DSS mice and reprogramed lipid metabolism partly through HIF1α/SREBP-1.


Assuntos
Neoplasias Colorretais/prevenção & controle , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Triterpenos/farmacologia , Animais , Anticarcinógenos/farmacologia , Azoximetano/toxicidade , Colite/induzido quimicamente , Colite/complicações , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/patologia , Sulfato de Dextrana/toxicidade , Células HCT116 , Células HT29 , Humanos , Masculino , Camundongos Endogâmicos BALB C , Fator de Necrose Tumoral alfa/genética , beta Catenina/genética
20.
Phytomedicine ; 63: 152968, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31280140

RESUMO

BACKGROUND: Gastric cancer has a high morbidity and is a leading cause of cancer-related mortality worldwide. Helicobacter pylori (H. pylori) infection is commonly found in the early stage of gastric cancer pathogenesis, which induces chronic gastritis. Artemisinin (ART) and its derivatives (ARTS, artesunate and DHA, dihydroartemisinin), a new class of potent antimalarials, have been reported to exert both preventive and anti-gastric cancer effects. However, the underlying mechanisms of the chemopreventive effects of ART and its derivatives in H. pylori infection induced-gastric cancer are not fully elucidated. PURPOSE: We investigated the effects of H. pylori infection in gastric cancer; and the preventive mechanisms of ART, ARTS and DHA. METHODS: The H. pylori growth was determined by the broth macro-dilution method, and its adhesion to gastric cancer cells was evaluated by using the urease assay. The protein and mRNA levels, reactive oxygen species (ROS) production, as well as the production of inflammatory cytokines were evaluated by Western blot, real-time PCR, flow cytometry and ELISA, respectively. Moreover, an in vivo MNU (N-methyl-N-nitroso-urea) and H. pylori-induced gastric adenocarcinoma mouse model was established for the investigation of the cancer preventive effects of ART and its derivaties, and the underlying mechanisms of action. RESULTS: ART, DHA and ARTS inhibited the growth of H. pylori and gastric cancer cells,suppressed H. pylori adhesion to the gastric cancer cells, and reduced the H. pylori-enhanced ROS production. Moreover, ART, DHA and ARTS significantly reduced tumor incidence, number of tumor nodules and tumor size in the mouse model. Among these three compounds, DHA exerted the most potent chemopreventive effect. Mechanistic studies showed that ART and its derivatives potently inhibited the NF-κB activation. CONCLUSION: ART, DHA and ARTS have potent preventive effects in H. pylori-induced gastric carcinogenesis. These effects are, at least in part, attributed to the inhibition of NF-κB signaling pathway. Our findings provide a molecular justification of using ART and its derivatives for the prevention and treatment of gastric cancer.


Assuntos
Anticarcinógenos/farmacologia , Artemisininas/farmacologia , Infecções por Helicobacter/complicações , Helicobacter pylori/efeitos dos fármacos , Neoplasias Gástricas/prevenção & controle , Animais , Artesunato/farmacologia , Aderência Bacteriana/efeitos dos fármacos , Linhagem Celular Tumoral , Citocinas/metabolismo , Helicobacter pylori/patogenicidade , Humanos , Camundongos Endogâmicos C57BL , Testes de Sensibilidade Microbiana , NF-kappa B/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Neoplasias Gástricas/microbiologia , Neoplasias Gástricas/patologia
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