RESUMO
The current research employed an animal model of 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary gland carcinogenesis. The estrogen receptor-positive human breast adenocarcinoma cell line (MCF-7) was used for in vitro analysis. This was combined with a network pharmacology-based approach to assess the anticancer properties of Spirulina (SP) extract and understand its molecular mechanisms. The results showed that the administration of 1 g/kg of SP increased the antioxidant activity by raising levels of catalase (CAT) and superoxide dismutase (SOD), while decreasing the levels of malonaldehyde (MDA) and protein carbonyl. A histological examination revealed reduced tumor occurrence, decreased estrogen receptor expression, suppressed cell proliferation, and promoted apoptosis in SP protected animals. In addition, SP disrupted the G2/M phase of the MCF-7 cell cycle, inducing apoptosis and reactive oxygen species (ROS) accumulation. It also enhanced intrinsic apoptosis in MCF-7 cells by upregulating cytochrome c, Bax, caspase-8, caspase-9, and caspase-7 proteins, while downregulating Bcl-2 production. The main compounds identified in the LC-MS/MS study of SP were 7-hydroxycoumarin derivatives of cinnamic acid, hinokinin, valeric acid, and α-linolenic acid. These substances specifically targeted three important proteins: ERK1/2 MAPK, PI3K-protein kinase B (AKT), and the epidermal growth factor receptor (EGFR). Network analysis and molecular docking indicated a significant binding affinity between SP and these proteins. This was verified by Western blot analysis that revealed decreased protein levels of p-EGFR, p-ERK1/2, and p-AKT following SP administration. SP was finally reported to suppress MCF-7 cell growth and induce apoptosis by modulating the PI3K/AKT/EGFR and MAPK signaling pathways suggesting EGFR as a potential target of SP in breast cancer (BC) treatment.
Assuntos
Apoptose , Neoplasias da Mama , Farmacologia em Rede , Spirulina , Spirulina/química , Humanos , Células MCF-7 , Animais , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Antineoplásicos/farmacologia , Camundongos , Antioxidantes/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Receptores ErbB/metabolismo , Transdução de Sinais/efeitos dos fármacos , Simulação de Acoplamento MolecularRESUMO
Excessive carbon emissions, especially CO2 release, have been a global concern. Few studies applied nanotechnology to relieve the ecotoxicity of CO2. Here, we applied carbon dots (CDs) to neutralize the CO2. We found CO2 induced the aggregation of CDs, which is of significance for CDs in enhanced fluorescence intensity but decreased CDs function in nanozyme activity, and reduced CDs toxicity to bacteria and cancer cells. Our data suggest the concern of CO2 release in global health in CDs mediated anticancer drug delivery and antibiotics resistance. However, enhanced fluorescence in cells which can be applied for bioimaging or CO2 sensing as simulated investigation by static charged attraction of positively charged CDs with negatively charged soluble HCO3-. Thus, CO2 abrogates the nanomedicine efficacy in cancer cells and antibacterial and may induce drug resistance for patients undergoing chemotherapy or antibiotics therapy. To overcome the resistance, we may apply the CDs for a neutralization of CO2 for impact on anticancer nanomedicine and antibiotics and reducing the ecotoxicity in biological systems.
Assuntos
Nanopartículas , Pontos Quânticos , Humanos , Antibacterianos/farmacologia , Dióxido de Carbono/farmacologia , Nanomedicina , Sistemas de Liberação de Medicamentos/métodosRESUMO
BACKGROUND: Ischemic injury is a common mechanism in both ischemic stroke (IS) and acute coronary syndrome (ACS). Matrix metalloproteinase 9 (MMP-9), an endopeptidase that degrades extracellular matrix, is important in the pathogenesis of IS. The purpose of this study is to evaluate the association between the SNP rs17576 in MMP-9 gene with (1) the risk and severity of acute ischemic stroke in Saudi Arab individuals with recent acute coronary syndrome, and (2) the risk of acute coronary syndrome in Saudi Arab individuals without ischemic stroke. METHODS: A case control study of 200 IS patients, 520 ACS patients (without IS), and 500 aged-matched healthy controls were genotyped to detect the MMP-9 polymorphism rs17156. RESULTS: Our study demonstrated a non-significant difference in the genotype and allele frequencies of the MMP9 rs17576 polymorphism between the patients with IS and patients with ACS without IS (P = 0.31 for the GA genotype, 0.25 for the AA genotype and P = 0.20 for the A allele). AA genotype was found to be statistically significant between IS and control groups; [OR=1.84, 95 % CI (1.08-3.14), p =0.015]. A allele showed a significant difference between the two groups [OR=1.28, 95 % CI (1.00-1.64), p =0.028]. By comparing ACS without IS and controls, AA genotype was significant [OR=1.46, 95 % CI (1.01-2.12), p =0.029]. Stratification by NIHSS score revealed higher mortality and early neurologic deterioration in IS patients with NIHSS score ≥ 16 (p < 0.001, 0.044 respectively). CONCLUSION: We deduced the lack of association either with allele or genotype frequencies (p>0.05) between the IS cases and the cases of ACS without IS. In contrast there was a significant association of mutant genotype AA between either the IS group or ACS (without IS) group, and the control group. In addition, different rs17576 genotypes were not associated with raised mortality or a tendency to develop early neurologic deterioration.
Assuntos
Síndrome Coronariana Aguda , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , AVC Isquêmico , Metaloproteinase 9 da Matriz , Polimorfismo de Nucleotídeo Único , Índice de Gravidade de Doença , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Síndrome Coronariana Aguda/genética , Síndrome Coronariana Aguda/diagnóstico , Síndrome Coronariana Aguda/mortalidade , AVC Isquêmico/genética , AVC Isquêmico/diagnóstico , AVC Isquêmico/mortalidade , Estudos de Casos e Controles , Metaloproteinase 9 da Matriz/genética , Idoso , Fatores de Risco , Medição de Risco , Arábia Saudita , FenótipoRESUMO
The most significant serotype of Shiga-toxigenic Escherichia coli that causes foodborne illnesses is Escherichia coli O157:H7. Elimination of E. coli O157:H7 during food processing and storage is a possible solution. Bacteriophages have a significant impact on bacterial populations in nature due to their ability to lyse their bacterial host. In the current study, a virulent bacteriophage, Ec_MI-02, was isolated from the feces of a wild pigeon in the United Arab Emirates (UAE) for potential future use as a bio-preservative or in phage therapy. Using a spot test and an efficiency of plating analysis, Ec_MI-02 was found to infect in addition to the propagation host, E. coli O157:H7 NCTC 12900, five different serotypes of E. coli O157:H7 (three clinical samples from infected patients, one from contaminated green salad, and one from contaminated ground beef). Based on morphology and genome analysis, Ec_MI-02 belongs to the genus Tequatrovirus under the order Caudovirales. The adsorption rate constant (K) of Ec_MI-02 was found to be 1.55 × 10-8 mL/min. The latent period was 50 min with a burst size of almost 10 plaque forming units (pfu)/host cell in the one-step growth curve when the phage Ec_MI-02 was cultivated using the propagation host E. coli O157:H7 NCTC 12900. Ec_MI-02 was found to be stable at a wide range of pH, temperature, and commonly used laboratory disinfectants. Its genome is 165,454 bp long with a GC content of 35.5% and encodes 266 protein coding genes. Ec_MI-02 has genes encoding for rI, rII, and rIII lysis inhibition proteins, which supports the observation of delayed lysis in the one-step growth curve. The current study provides additional evidence that wild birds could also be a good natural reservoir for bacteriophages that do not carry antibiotic resistance genes and could be good candidates for phage therapy. In addition, studying the genetic makeup of bacteriophages that infect human pathogens is crucial for ensuring their safe usage in the food industry.
Assuntos
Bacteriófagos , Escherichia coli O157 , Animais , Bovinos , Humanos , Escherichia coli O157/genética , Escherichia coli O157/metabolismo , Columbidae , Myoviridae/genética , Bacteriófagos/genética , Genômica , FezesRESUMO
Despite being a potent anticancer drug, cisplatin has limited applicability due to its adverse effects, such as testicular damage. Consequently, reducing its toxicity becomes necessary. In this study, a selective phosphodiesterase-3 inhibitor, cilostazol, which is used to treat intermittent claudication, was examined for its ability to abrogate cisplatin-induced testicular toxicity. Its ameliorative effect was compared to that of two phosphodiesterase inhibitors, tadalafil and pentoxifylline. The study also focused on the possible mechanisms involved in the proposed protective effect. Cisplatin-treated rats showed a significant decrease in sperm number and motility, serum testosterone, and testicular glutathione levels, as well as a significant elevation in malondialdehyde, total nitrite levels, and the protein expression of tumor necrosis factor-alpha, nuclear factor-kappa ß, and caspase-3. These outcomes were confirmed by marked testicular architecture deterioration. Contrary to this, cilostazol, in a dose-dependent manner, showed potential protection against testicular toxicity, reversed the disrupted testicular function, and improved histological alterations through rebalancing of oxidative stress, inflammation, and apoptosis. In addition, cilostazol exerted a more pronounced protective effect in comparison to tadalafil and pentoxifylline. In conclusion, cilostazol ameliorates cisplatin-induced testicular impairment through alteration of oxidative stress, inflammation, and apoptotic pathways, offering a promising treatment for cisplatin-induced testicular damage.
Assuntos
NF-kappa B , Pentoxifilina , Masculino , Animais , Ratos , Cilostazol/farmacologia , Fator de Necrose Tumoral alfa , Cisplatino/toxicidade , Caspase 3 , Pentoxifilina/farmacologia , Tadalafila , Sêmen , Estresse Oxidativo , Inibidores da Fosfodiesterase 3 , InflamaçãoRESUMO
Liver cancer remains among the leading causes of cancer-related deaths worldwide. This is due to many reasons, including limitations of available drugs, late diagnosis due to the overlapping symptoms with many other liver diseases, and lack of effective screening modalities. Compared to conventional chemotherapy, targeted drug delivery systems are advantageous in many ways, as they minimize drug resistance and improve therapeutic value for cancer patients. Nanomaterials, in general, and nanoparticles, in particular, possess nm size, which provides a high surface area for a great extent of functionalization to be used for the targeted delivery of cancer drugs. Amongst the different formulations of nanoparticles, magnetic nanoparticles (MNPs) have unique chemical and physical characteristics and magnetic behavior, making them preferable candidates as a core for drug delivery systems. To maintain the nanosized structure of MNPs, a polymeric coating is usually applied to maintain the nanoparticles dispersed in the solution. Moreover, the polymeric coating provides a plate form for carrying drug molecules on its surface. In the present study, poly(ethylene glycol) (PEG)-coated MNPs were successfully synthesized, where the optimum concentration of PEG on the surface of the MNPs was investigated. The PEG-coated MNPs were further coated with crocetin at different concentrations. The crocetin-coated pegylated MNPs were evaluated in vitro using a hepatic cell line (HepG2) for up to 72 h. Results showed good release kinetics under acidic and neutral conditions. The optimally prepared drug delivery system showed a high potential for reducing the HepG2 cell proliferation in vitro using an MTT assay. The calculated IC50 for Cro-PEG-MNPs were 0.1019, 0.0903, and 0.0462 mg/mL of 5×, 10× and 20×, respectively.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Nanopartículas de Magnetita , Nanopartículas , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Nanopartículas de Magnetita/química , Neoplasias Hepáticas/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Polímeros/uso terapêutico , Polietilenoglicóis/químicaRESUMO
Verotoxin-producing Escherichia coli O157:H7 is responsible for the majority of foodborne outbreaks worldwide and may lead to death. Bacteriophages are natural killers of bacteria. All previously reported E. coli O157:H7 phages were isolated from ruminants or swine. Here, we report for the first time a phage isolated from bird feces in the United Arab Emirates (UAE), designated as UAE_MI-01, indicating birds as a good source of phages. Thus, phages could be a tool for predicting the presence of the host bacteria in an animal or the environment. UAE_MI-01 was found to be a lytic phage that was stable at wide ranges of pH, temperature, and chemical disinfectants, and with a burst size of almost 100 plaque-forming units per host cell after a latent period of 20 min and an adsorption rate constant (K) of 1.25 × 10-7 mL min-1. The phage genome was found to be 44,281 bp long with an average GC content of 54.7%. The presence of the phage indicates the presence of the host cell E. coli O157:H7 in wild birds. Therefore, other birds, mainly poultry, could be also investigated for the presence of this pathogenic bacterium. To the best of our knowledge, this is the first report of an E. coli O157:H7 bacteriophage isolated from a bird.
Assuntos
Bacteriófagos , Escherichia coli O157 , Animais , Suínos , Escherichia coli O157/genética , Bacteriófagos/genética , Emirados Árabes Unidos , Genoma , Genômica , RuminantesRESUMO
Sorafenib is the first drug approved to treat advanced hepatocellular carcinoma (HCC) and continues as the gold-standard therapy against HCC. However, acquired drug resistance represents a main concern about sorafenib therapy. The flavanol quercetin found in plants has shown great anti-cancer and anti-inflammatory properties. In this work, quercetin was used as a therapeutic agent alone or in combination with a sorafenib chemotherapy drug to improve the routine HCC treatment with sorafenib. The in vitro and in vivo results presented here confirm that quercetin alone or in combination with sorafenib significantly inhibited HCC growth, induced cell cycle arrest and induced apoptosis and necrosis. Further molecular data shown in this report demonstrate that quercetin alone or combined with sorafenib downregulated key inflammatory, proliferative and angiogenesis-related genes (TNF-α, VEGF, P53 and NF-κB). Combined quercetin/sorafenib treatment markedly improved the morphology of the induced liver damage and showed significant antioxidant and anti-tumor effects. The advantage of combined treatment efficacy reported here can be attributed to quercetin's prominent effects in modulating cell cycle arrest, apoptosis, oxidative stress and inflammation.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Carcinoma Hepatocelular/metabolismo , Quercetina/farmacologia , Quercetina/uso terapêutico , Neoplasias Hepáticas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Linhagem Celular TumoralRESUMO
RNA isolation from bacteria is technically difficult due to the RNA characteristic of labile and vulnerable degradation. Many reagents were explored for cellular lysis and complete inhibition of RNase. However, the available methods for RNA isolation are either of low efficiency or time-consuming. Here, we developed a rapid and accessible protocol for RNA isolation that combined a simplified cell lysis and RNA release by formamide-based solution and RNA purification by chitosan-modified silica membrane for the first time. With this method, we obtained about ~ 28 µg of total RNA from 108 Escherichia coli cells. The entire procedure can be done within 15 min without redundant pipetting steps. The purity of extracted RNA was comparable to that of commercial kits, but the cost was much lower. Furthermore, the yielded RNA was successfully used in downstream enzymatic reactions, such as reverse transcription and quantitative real-time PCR. This new method would be of benefit for an extensive range of gene expression analyses in bacterial organisms.
Assuntos
Quitosana/análogos & derivados , Escherichia coli/química , Formamidas/química , RNA Bacteriano/isolamento & purificação , Dióxido de Silício/química , Escherichia coli/genética , Membranas Artificiais , RNA Bacteriano/genéticaRESUMO
This report explores the available curative molecules directed against hepatocellular carcinoma (HCC). Limited efficiency as well as other drawbacks of existing molecules led to the search for promising potential alternatives. Understanding of the cell signaling mechanisms propelling carcinogenesis and driven by cell proliferation, invasion, and angiogenesis can offer valuable information for the investigation of efficient treatment strategies. The complexity of the mechanisms behind carcinogenesis inspires researchers to explore the ability of various biomolecules to target specific pathways. Natural components occurring mainly in food and medicinal plants, are considered an essential resource for discovering new and promising therapeutic molecules. Novel biomolecules normally have an advantage in terms of biosafety. They are also widely diverse and often possess potent antioxidant, anti-inflammatory, and anti-cancer properties. Based on quantitative structure-activity relationship studies, biomolecules can be used as templates for chemical modifications that improve efficiency, safety, and bioavailability. In this review, we focus on anti-HCC biomolecules that have their molecular targets partially or completely characterized as well as having anti-cancer molecular mechanisms that are fairly described.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Terapia de Alvo Molecular , Proteínas de Neoplasias/antagonistas & inibidores , Animais , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologiaRESUMO
BACKGROUND: Colorectal cancer (CRC) is one of the most common cancers worldwide. One of its subtypes is associated with defective mismatch repair (dMMR) genes. Saffron has many potentially protective roles against colon malignancy. However, these roles in the context of dMMR tumors have not been explored. In this study, we aimed to investigate the effects of saffron and its constituents in CRC cell lines with dMMR. METHODS: Saffron crude extracts and specific compounds (safranal and crocin) were used in the human colorectal cancer cell lines HCT116, HCT116+3 (inserted MLH1), HCT116+5 (inserted MSH3), and HCT116+3+5 (inserted MLH1 and MSH3). CDC25b, p-H2AX, TPDP1, and GAPDH were analyzed by Western blot. Proliferation and cytotoxicity were analyzed by MTT. The scratch wound assay was also performed. RESULTS: Saffron crude extracts restricted (up to 70%) the proliferation in colon cells with deficient MMR (HCT116) compared to proficient MMR. The wound healing assay indicates that deficient MMR cells are doing better (up to 90%) than proficient MMR cells when treated with saffron. CDC25b and TDP1 downregulated (up to 20-fold) in proficient MMR cells compared to deficient MMR cells, while p.H2AX was significantly upregulated in both cell types, particularly at >10 mg/mL saffron in a concentration-dependent manner. The reduction in cellular proliferation was accompanied with upregulation of caspase 3 and 7. The major active saffron compounds, safranal and crocin reproduced most of the saffron crude extracts' effects. CONCLUSIONS: Saffron's anti-proliferative effect is significant in cells with deficient MMR. This novel effect may have therapeutic implications and benefits for MSI CRC patients who are generally not recommended for the 5-fluorouracil-based treatment.
Assuntos
Neoplasias do Colo/tratamento farmacológico , Crocus/química , Reparo de Erro de Pareamento de DNA/efeitos dos fármacos , Instabilidade de Microssatélites/efeitos dos fármacos , Extratos Vegetais/farmacologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Células HCT116 , Humanos , Extratos Vegetais/químicaRESUMO
BACKGROUND: Coronary artery disease (CAD) is one of the common genetic and clinical risk factors associated with cardiovascular and multifactorial disorder. ATP-binding cassette transporter A1 (ABCA1) gene plays an important role in lipid metabolism and in multiple studies associated with CAD. However, more studies are needed to identify the exact role of single nucleotide polymorphisms which may cause CAD. OBJECTIVES: The aim of this study is to investigate the genetic association of polymorphism g.1051G > A in the ABCA1 gene with CAD patients in the Saudi population. METHODS: We included 315 confirmed CAD cases, and 205 non-CAD or control subjects in this case-control study. DNA isolation was carried out for all registered participants and the polymorphism g.1051G > A was genotyped with Polymerase Chain Reaction followed by Restriction Fragment Length Polymorphism analysis with EcoNI restriction enzyme. RESULTS: Modifiable risk factors such as Body Mass Index, smoking and diabetes were strongly associated and non-modifiable risk factors such as hypertension (Systolic Blood Pressure and Diastolic Blood Pressure) and serum analysis such as Fasting Blood Glucose, Total cholesterol (TC), Triglyceride (TG) and LDL-c were significantly associated in CAD cases (p < 0.05). Allele (OR-1.73;95% CI:1.33-2.26; p = 0.0004), GA vs GG (OR-2.26; 95% CI: 1.53-3.35; p = 0.0003 and dominant inheritance pattern (OR-2.23; 95% CI:1.56-3.20; p = 0.00009 was strongly associated with CAD cases and control subjects. The frequency level of use of atorvastatin was significantly different among GG, GA and AA subjects. Additionally, TC and TG levels were influenced by the presence of g.1051G > A polymorphism. CONCLUSION: The polymorphism g.1051G > A in the gene ABCA1 is closely associated with the existence of the CAD subjects. This polymorphism could also affect the serum levels of the lipid profile, suggesting a possible occurrence of CAD in the Saudi population.
RESUMO
BACKGROUND: Elevated plasma triglycerides (TGs) are widely used as a major cardiovascular risk predictor and are thought to play an important role in the progression of coronary heart disease (CHD). It has been demonstrated that lipid lowering was associated with lower mortality in patients with CHD. The present study therefore aimed to investigate the consequences of the genetic variant c.553G > T (rs2075291) in apolipoprotein A5 gene to determination of triglycerides levels in CAD patients receiving, atorvastatin, lipid lowering drug. METHODS: We here report that a recently identified genetic variant, c.553G > T in the APOA5 gene which causes a substitution of a cysteine for a glycine residue at amino acid residue 185(G185C) is also associated with increased TG levels. To investigate theses effects, a case-control study compressing 608 subjects from the same area was performed. RESULTS: TG levels in T allele patients were significantly lower than the control GT allele patient (χ2 = 2.382E2a, P-value < 0.001). Overall, patients carrying T allele showed lower levels of TG than patients carrying GG allele. The homozygous patient for the T allele presented normal cholesterol levels of 134 mg/dl, and the levels in GG patients ranged from 25 to 340 mg/dl (P-value < 0.001). In summary, we demonstrated that the presence of c.553G > T variant (rs2075291); in APOA5 gene increases human plasma TG levels. CONCLUSION: Nevertheless, T allele is found to reduce TG levels in CAD patients who are on the cholesterol medication, atorvastatin. Thus, c.553G > T variant can be considered as a significant predicator of hypertriglyceridemia. In addition, it could be used as a hallmark for the diagnosis and prognosis of CAD.
Assuntos
Apolipoproteína A-V/genética , Atorvastatina/uso terapêutico , Doença da Artéria Coronariana/genética , Variação Genética , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipertrigliceridemia/genética , Triglicerídeos/sangue , Adulto , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/tratamento farmacológico , Feminino , Predisposição Genética para Doença , Humanos , Hipertrigliceridemia/sangue , Hipertrigliceridemia/diagnóstico , Hipertrigliceridemia/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Fenótipo , Resultado do Tratamento , Adulto JovemRESUMO
This report describes an investigation of camel whey protein hydrolysates (CWPH) produced by gastric and pancreatic enzymes for their in vitro antidiabetic, anticancer, and anti-inflammatory properties. Degree of hydrolysis (DH) ranged from 8.54 to 47.53%, with hydrolysates generated using chymotrypsin for 6 h displaying the highest DH. Reverse phase-HPLC analysis showed that α-lactalbumin underwent complete degradation, with no intact α-lactalbumin detected in CWPH. The CWPH displayed enhanced antidiabetic activity compared with intact whey proteins; with pepsin- and chymotrypsin-generated CWPH displaying greater inhibition of dipeptidyl peptidase IV (DPP-IV), α-glucosidase, and α-amylase compared with trypsin-generated CWPH. The highest antiproliferative effect was observed for CWPH generated by chymotrypsin for 3 h, with only 4.5 to 6.5% viable liver cancer cells (HepG2) remaining when tested at concentrations from 400 to 1,000 µg/mL. The highest anti-inflammatory activity was manifested by CWPH generated by pepsin at 6-h hydrolysis. We report enhanced antiproliferative, antidiabetic, and anti-inflammatory activities upon hydrolysis of camel whey proteins, indicating their potential utilization as bioactive and functional ingredients.
Assuntos
Camelus , Inibidores da Dipeptidil Peptidase IV/farmacologia , Inflamação/tratamento farmacológico , Proteínas do Soro do Leite/farmacologia , Animais , Hidrólise , Neoplasias Hepáticas , Proteínas do Leite , Hidrolisados de Proteína , Células Tumorais CultivadasRESUMO
BACKGROUND: Here, we determined in vitro antioxidant activity, total phenols and flavonoids and evaluated antiproliferative activity of three medicinal plant extracts: Trigonella foenum-graecum (Fenugreek), Cassia acutifolia (Senna) and Rhazya stricta (Harmal). METHODS: The leaves of the three medicinal plants were extracted with 70% ethanol. Antioxidant activities of the extracts were determined by using DPPH (1,1-diphenyl-2-picrylhydrazyl) assay. Total flavonoid and phenolic contents were determined using colorimetric assays. MTT assay was used to estimate the antiproliferative activities of the extracts against human hepatoma (HepG2) cancer cell line. In addition, the effects of R. stricta extract on cell cycle, colony formation, and wound healing of HepG2 cells and tube formation of HUVEC cells were assessed. RESULTS: Percentage inhibition of DPPH scavenging activity were dose-dependent and ranged between (89.9% ± 0.51) and (28.6% ± 2.07). Phenolic contents ranged between (11.5 ± 0.013) and (9.7 ± 0.008) mg GAE/g while flavonoid content ranged between (20.8 ± 0.40) and (0.12 ± 0.0.01) mg QE/g. Antiproliferative results of the extracts were found to be consistent with their antioxidant activity. Among the extracts evaluated, that of R. stricta showed the best antioxidant, antiproliferative and antimetastatic activities at low concentration. It also inhibited the colony-formation capacity of HepG2 cells and exhibited antiangiogenic activity. Cell cycle analysis showed significant arrest of cells at G2/M phase 12 and 48 h after treatment and significant arrest at G1/S phase after 24 h of treatment. Consistent data were observed in western blot analysis of protein levels of Cdc2 and its cyclin partners. CONCLUSIONS: These findings introduce R. stricta as a potentially useful anti-metastatic agent and a novel potential anti-tumour agent for hepatocellular carcinoma (HCC) treatment.
Assuntos
Antineoplásicos , Antioxidantes , Fabaceae/química , Extratos Vegetais , Antineoplásicos/química , Antineoplásicos/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Compostos de Bifenilo/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Flavonoides/análise , Células Hep G2 , Células Endoteliais da Veia Umbilical Humana , Humanos , Medicina Tradicional , Fenóis/análise , Picratos/metabolismo , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Plantas Medicinais/químicaRESUMO
One of the hallmarks of malignant cell populations is the ability to undergo continuous proliferation. This property allows clonal lineages to acquire sequential aberrations that can fuel increasingly autonomous growth, invasiveness, and therapeutic resistance. Innate cellular mechanisms have evolved to regulate replicative potential as a hedge against malignant progression. When activated in the absence of normal terminal differentiation cues, these mechanisms can result in a state of persistent cytostasis. This state, termed "senescence," can be triggered by intrinsic cellular processes such as telomere dysfunction and oncogene expression, and by exogenous factors such as DNA damaging agents or oxidative environments. Despite differences in upstream signaling, senescence often involves convergent interdependent activation of tumor suppressors p53 and p16/pRB, but can be induced, albeit with reduced sensitivity, when these suppressors are compromised. Doses of conventional genotoxic drugs required to achieve cancer cell senescence are often much lower than doses required to achieve outright cell death. Additional therapies, such as those targeting cyclin dependent kinases or components of the PI3K signaling pathway, may induce senescence specifically in cancer cells by circumventing defects in tumor suppressor pathways or exploiting cancer cells' heightened requirements for telomerase. Such treatments sufficient to induce cancer cell senescence could provide increased patient survival with fewer and less severe side effects than conventional cytotoxic regimens. This positive aspect is countered by important caveats regarding senescence reversibility, genomic instability, and paracrine effects that may increase heterogeneity and adaptive resistance of surviving cancer cells. Nevertheless, agents that effectively disrupt replicative immortality will likely be valuable components of new combinatorial approaches to cancer therapy.
Assuntos
Proliferação de Células/genética , Senescência Celular/genética , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/genética , Antineoplásicos/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Instabilidade Genômica/efeitos dos fármacos , Humanos , Neoplasias/patologia , Fosfatidilinositol 3-Quinases/genética , Transdução de Sinais/genética , Telomerase/efeitos dos fármacos , Telomerase/genética , Proteína Supressora de Tumor p53/genéticaRESUMO
Deregulation of angiogenesis--the growth of new blood vessels from an existing vasculature--is a main driving force in many severe human diseases including cancer. As such, tumor angiogenesis is important for delivering oxygen and nutrients to growing tumors, and therefore considered an essential pathologic feature of cancer, while also playing a key role in enabling other aspects of tumor pathology such as metabolic deregulation and tumor dissemination/metastasis. Recently, inhibition of tumor angiogenesis has become a clinical anti-cancer strategy in line with chemotherapy, radiotherapy and surgery, which underscore the critical importance of the angiogenic switch during early tumor development. Unfortunately the clinically approved anti-angiogenic drugs in use today are only effective in a subset of the patients, and many who initially respond develop resistance over time. Also, some of the anti-angiogenic drugs are toxic and it would be of great importance to identify alternative compounds, which could overcome these drawbacks and limitations of the currently available therapy. Finding "the most important target" may, however, prove a very challenging approach as the tumor environment is highly diverse, consisting of many different cell types, all of which may contribute to tumor angiogenesis. Furthermore, the tumor cells themselves are genetically unstable, leading to a progressive increase in the number of different angiogenic factors produced as the cancer progresses to advanced stages. As an alternative approach to targeted therapy, options to broadly interfere with angiogenic signals by a mixture of non-toxic natural compound with pleiotropic actions were viewed by this team as an opportunity to develop a complementary anti-angiogenesis treatment option. As a part of the "Halifax Project" within the "Getting to know cancer" framework, we have here, based on a thorough review of the literature, identified 10 important aspects of tumor angiogenesis and the pathological tumor vasculature which would be well suited as targets for anti-angiogenic therapy: (1) endothelial cell migration/tip cell formation, (2) structural abnormalities of tumor vessels, (3) hypoxia, (4) lymphangiogenesis, (5) elevated interstitial fluid pressure, (6) poor perfusion, (7) disrupted circadian rhythms, (8) tumor promoting inflammation, (9) tumor promoting fibroblasts and (10) tumor cell metabolism/acidosis. Following this analysis, we scrutinized the available literature on broadly acting anti-angiogenic natural products, with a focus on finding qualitative information on phytochemicals which could inhibit these targets and came up with 10 prototypical phytochemical compounds: (1) oleanolic acid, (2) tripterine, (3) silibinin, (4) curcumin, (5) epigallocatechin-gallate, (6) kaempferol, (7) melatonin, (8) enterolactone, (9) withaferin A and (10) resveratrol. We suggest that these plant-derived compounds could be combined to constitute a broader acting and more effective inhibitory cocktail at doses that would not be likely to cause excessive toxicity. All the targets and phytochemical approaches were further cross-validated against their effects on other essential tumorigenic pathways (based on the "hallmarks" of cancer) in order to discover possible synergies or potentially harmful interactions, and were found to generally also have positive involvement in/effects on these other aspects of tumor biology. The aim is that this discussion could lead to the selection of combinations of such anti-angiogenic compounds which could be used in potent anti-tumor cocktails, for enhanced therapeutic efficacy, reduced toxicity and circumvention of single-agent anti-angiogenic resistance, as well as for possible use in primary or secondary cancer prevention strategies.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias/terapia , Neovascularização Patológica/terapia , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/crescimento & desenvolvimento , Vasos Sanguíneos/patologia , Proliferação de Células/efeitos dos fármacos , Humanos , Imunoterapia , Neoplasias/prevenção & controle , Neovascularização Patológica/prevenção & controleRESUMO
Genomic instability can initiate cancer, augment progression, and influence the overall prognosis of the affected patient. Genomic instability arises from many different pathways, such as telomere damage, centrosome amplification, epigenetic modifications, and DNA damage from endogenous and exogenous sources, and can be perpetuating, or limiting, through the induction of mutations or aneuploidy, both enabling and catastrophic. Many cancer treatments induce DNA damage to impair cell division on a global scale but it is accepted that personalized treatments, those that are tailored to the particular patient and type of cancer, must also be developed. In this review, we detail the mechanisms from which genomic instability arises and can lead to cancer, as well as treatments and measures that prevent genomic instability or take advantage of the cellular defects caused by genomic instability. In particular, we identify and discuss five priority targets against genomic instability: (1) prevention of DNA damage; (2) enhancement of DNA repair; (3) targeting deficient DNA repair; (4) impairing centrosome clustering; and, (5) inhibition of telomerase activity. Moreover, we highlight vitamin D and B, selenium, carotenoids, PARP inhibitors, resveratrol, and isothiocyanates as priority approaches against genomic instability. The prioritized target sites and approaches were cross validated to identify potential synergistic effects on a number of important areas of cancer biology.
Assuntos
Instabilidade Genômica/efeitos dos fármacos , Neoplasias/dietoterapia , Neoplasias/genética , Centrossomo/metabolismo , Dano ao DNA/genética , Reparo do DNA/genética , Dieta , Instabilidade Genômica/genética , Humanos , Neoplasias/patologia , Prognóstico , Telomerase/antagonistas & inibidores , Telomerase/genéticaRESUMO
The evasion of anti-growth signaling is an important characteristic of cancer cells. In order to continue to proliferate, cancer cells must somehow uncouple themselves from the many signals that exist to slow down cell growth. Here, we define the anti-growth signaling process, and review several important pathways involved in growth signaling: p53, phosphatase and tensin homolog (PTEN), retinoblastoma protein (Rb), Hippo, growth differentiation factor 15 (GDF15), AT-rich interactive domain 1A (ARID1A), Notch, insulin-like growth factor (IGF), and Krüppel-like factor 5 (KLF5) pathways. Aberrations in these processes in cancer cells involve mutations and thus the suppression of genes that prevent growth, as well as mutation and activation of genes involved in driving cell growth. Using these pathways as examples, we prioritize molecular targets that might be leveraged to promote anti-growth signaling in cancer cells. Interestingly, naturally occurring phytochemicals found in human diets (either singly or as mixtures) may promote anti-growth signaling, and do so without the potentially adverse effects associated with synthetic chemicals. We review examples of naturally occurring phytochemicals that may be applied to prevent cancer by antagonizing growth signaling, and propose one phytochemical for each pathway. These are: epigallocatechin-3-gallate (EGCG) for the Rb pathway, luteolin for p53, curcumin for PTEN, porphyrins for Hippo, genistein for GDF15, resveratrol for ARID1A, withaferin A for Notch and diguelin for the IGF1-receptor pathway. The coordination of anti-growth signaling and natural compound studies will provide insight into the future application of these compounds in the clinical setting.
Assuntos
Carcinogênese/genética , Proliferação de Células/genética , Neoplasias/genética , Neoplasias/terapia , Transdução de Sinais , Proteínas de Ligação a DNA , Fator 15 de Diferenciação de Crescimento/genética , Via de Sinalização Hippo , Humanos , Fatores de Transcrição Kruppel-Like/genética , Terapia de Alvo Molecular , Proteínas Nucleares/genética , PTEN Fosfo-Hidrolase/genética , Proteínas Serina-Treonina Quinases/genética , Proteína do Retinoblastoma/genética , Somatomedinas/genética , Fatores de Transcrição/genética , Proteína Supressora de Tumor p53/genéticaRESUMO
Cancers harbor significant genetic heterogeneity and patterns of relapse following many therapies are due to evolved resistance to treatment. While efforts have been made to combine targeted therapies, significant levels of toxicity have stymied efforts to effectively treat cancer with multi-drug combinations using currently approved therapeutics. We discuss the relationship between tumor-promoting inflammation and cancer as part of a larger effort to develop a broad-spectrum therapeutic approach aimed at a wide range of targets to address this heterogeneity. Specifically, macrophage migration inhibitory factor, cyclooxygenase-2, transcription factor nuclear factor-κB, tumor necrosis factor alpha, inducible nitric oxide synthase, protein kinase B, and CXC chemokines are reviewed as important antiinflammatory targets while curcumin, resveratrol, epigallocatechin gallate, genistein, lycopene, and anthocyanins are reviewed as low-cost, low toxicity means by which these targets might all be reached simultaneously. Future translational work will need to assess the resulting synergies of rationally designed antiinflammatory mixtures (employing low-toxicity constituents), and then combine this with similar approaches targeting the most important pathways across the range of cancer hallmark phenotypes.