RESUMO
Garlic (Allium sativum L.) possesses numerous pharmacological potential, including antibacterial, antiarthritic, antithrombotic, anticancer, hypoglycemic, and hypolipidemic effects. The anti-cancer action of garlic is likely the best researched of the many advantageous pharmacological effects, and its use offers significant protection against the risk of developing cancer. A few active metabolites of garlic have been reported to be essential in the destruction of malignant cells due to their multi-targeted activities and lack of significant toxicity. The bioactive compounds in garlic having anticancer properties include diallyl trisulfide, allicin, allyl mercaptan diallyl disulfide, and diallyl sulphide. Different garlic-derived constituents and their nanoformulations have been tested for their effects against various cancers including skin, ovarian, prostate, gastric, breast, and lung, colorectal, liver, oral, and pancreatic cancer. The objective of this review is to summarize the antitumor activity and associated mechanisms of the organosulfur compounds of garlic in breast carcinoma. Breast cancer continues to have a significant impact on the total number of cancer deaths worldwide. Global measures are required to reduce its growing burden, particularly in developing nations where incidence is increasing quickly and fatality rates are still high. It has been demonstrated that garlic extract, its bioactive compounds, and their use in nanoformulations can prevent breast cancer in all of its stages, including initiation, promotion, and progression. Additionally, these bioactive compounds affect cell signaling for cell cycle arrest and survival along with lipid peroxidation, nitric oxide synthase activity, epidermal growth factor receptor, nuclear factor kappa B (NF-κB), and protein kinase C in breast carcinoma. Hence, this review deciphers the anticancer potential of garlic components and its nanoformulations against several breast cancer thereby projecting it as a potent drug candidate for efficient breast cancer management.
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Chemotherapeutics continue to play a central role in the treatment of a wide variety of cancers. Conventional chemotherapy involving bolus intravenous doses results in severe side effects - in some cases life threatening - delayed toxicity and compromised quality-of-life. Attempts to deliver small drug molecules using liposomes, polymeric nanoparticles, micelles, lipid nanoparticles, etc. have produced limited nanoformulations for clinical use, presumably due to a lack of biocompatibility of the material, costs, toxicity, scalability, and/or lack of effective administration. Naturally occurring small extracellular vesicles, or exosomes, may offer a solution and a viable system for delivering cancer therapeutics. Combined with their inherent trafficking ability and versatility of cargo capacity, exosomes can be engineered to specifically target cancerous cells, thereby minimizing off-target effects, and increasing the efficacy of cancer therapeutics. Exosomal formulations have mitigated the toxic effects of several drugs in murine cancer models. In this article, we review studies related to exosomal delivery of both small molecules and biologics, including siRNA to inhibit specific gene expression, in the pursuit of effective cancer therapeutics. We focus primarily on bovine milk and colostrum exosomes as the cancer therapeutic delivery vehicles based on their high abundance, cost effectiveness, scalability, high drug loading, functionalization of exosomes for targeted delivery, and lack of toxicity. While bovine milk exosomes may provide a new platform for drug delivery, extensive comparison to other nanoformulations and evaluation of long-term toxicity will be required to fully realize its potential.
Assuntos
Exossomos , Neoplasias , Feminino , Gravidez , Humanos , Animais , Camundongos , Leite , Colostro/metabolismo , Exossomos/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Sistemas de Liberação de MedicamentosRESUMO
Breast cancer (BC) is a leading cause of cancer deaths in women in less developed countries and the second leading cause of cancer death in women in the U.S. In this study, we report the inhibition of E2-mediated mammary tumorigenesis by Cuminum cyminum (cumin) administered via the diet as cumin powder, as well as dried ethanolic extract. Groups of female ACI rats were given either an AIN-93M diet or a diet supplemented with cumin powder (5% and 7.5%, w/w) or dried ethanolic cumin extract (1%, w/w), and then challenged with subcutaneous E2 silastic implants (1.2 cm; 9 mg). The first appearance of a palpable mammary tumor was significantly delayed by both the cumin powder and extract. At the end of the study, the tumor incidence was 96% in the control group, whereas only 55% and 45% animals had palpable tumors in the cumin powder and extract groups, respectively. Significant reductions in tumor volume (660 ± 122 vs. 138 ± 49 and 75 ± 46 mm3) and tumor multiplicity (4.21 ± 0.43 vs. 1.16 ± 0.26 and 0.9 ± 0.29 tumors/animal) were also observed by the cumin powder and cumin extract groups, respectively. The cumin powder diet intervention dose- and time-dependently offset E2-related pituitary growth, and reduced the levels of circulating prolactin and the levels of PCNA in the mammary tissues. Mechanistically, the cumin powder diet resulted in a significant reversal of E2-associated modulation in ERα, CYP1A1 and CYP1B1. Further, the cumin powder diet reversed the expression levels of miRNAs (miR-182, miR-375, miR-127 and miR-206) that were highly modulated by E2 treatment. We analyzed the composition of the extract by GC/MS and established cymene and cuminaldehyde as major components, and further detected no signs of gross or systemic toxicity. Thus, cumin bioactives can significantly delay and prevent E2-mediated mammary tumorigenesis in a safe and effective manner, and warrant continued efforts to develop these clinically translatable spice bioactives as chemopreventives and therapeutics against BC.
Assuntos
Cuminum/química , Estradiol/toxicidade , Estrogênios/toxicidade , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Mamárias Experimentais/prevenção & controle , Extratos Vegetais/farmacologia , Animais , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1B1/genética , Citocromo P-450 CYP1B1/metabolismo , Feminino , Neoplasias Mamárias Experimentais/induzido quimicamente , Neoplasias Mamárias Experimentais/patologia , MicroRNAs/genética , Ratos , Ratos Endogâmicos ACIRESUMO
Exosomes are unique biogenic nanocarriers of endocytic origin that are generated from most of the cells and found in biofluids like milk, plasma, saliva, and urine. Bovine milk represents the largest and an economic source for the production of exosomes. In recent past, the utility of the milk exosomes as drug carriers is intensified. Exosomes are emerging for delivery of both small and large therapeutics due to their biocompatibility. In this article, we highlighted the various exosomal isolation techniques, physicochemical properties, their biodistribution, and utility of milk exosomes in delivering the small drug molecules and siRNA to combat cancer.
Assuntos
Terapia Biológica/métodos , Sistemas de Liberação de Medicamentos/métodos , Exossomos/metabolismo , Leite/metabolismo , Neoplasias/terapia , Animais , Antineoplásicos/uso terapêutico , Humanos , Nanoestruturas , RNA Interferente Pequeno/uso terapêuticoRESUMO
Cervical cancer is caused by human papillomavirus (HPV). The disease develops over many years through a series of precancerous lesions. Cervical cancer can be prevented by HPV-vaccination, screening and treatment of precancer before development of cervical cancer. The treatment of high-grade cervical dysplasia (CIN 2+) has traditionally been by cervical conization. Surgical procedures are associated with increased risk of undesirable side effects including bleeding, infection, scarring (stenosis), infertility and complications in later pregnancies. An inexpensive, non-invasive method of delivering therapeutics locally will be favorable to treat precancerous cervical lesions without damaging healthy tissue. The feasibility and safety of a sustained, continuous drug-releasing cervical polymeric implant for use in clinical trials was studied using a large animal model. The goat (Capra hircus), non-pregnant adult female Boer goats, was chosen due to similarities in cervical dimensions to the human. Estrus was induced with progesterone CIDR® vaginal implants for 14days followed by the administration of chorionic gonadotropins 48h prior to removal of the progesterone implants to relax the cervix to allow for the placement of the cervical implant. Cervical implants, containing 2% and 4% withaferin A (WFA), with 8 coats of blank polymer, provided sustained release for a long duration and were used for the animal study. The 'mushroom'-shaped cervical polymeric implant, originally designed for women required redesigning to be accommodated within the goat cervix. The cervical implants were well tolerated by the animals with no obvious evidence of discomfort, systemic or local inflammation or toxicity. In addition, we developed a new method to analyze tissue WFA levels by solvent extractions and LS/MS-MS. WFA was found to be localized to the target and adjacent tissues with 12-16ng WFA/g tissue, with essentially no detectable WFA in distant tissues. This study suggests that the goat is a good large animal model for the future development and evaluation of therapeutic efficacy of continuous local drug delivery by cervical polymeric implants to treat precancerous cervical lesions.
Assuntos
Sistemas de Liberação de Medicamentos , Infecções por Papillomavirus/tratamento farmacológico , Displasia do Colo do Útero/tratamento farmacológico , Vitanolídeos/administração & dosagem , Animais , Modelos Animais de Doenças , Feminino , Cabras , Humanos , Papillomaviridae/patogenicidade , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/virologia , Gravidez , Displasia do Colo do Útero/complicações , Displasia do Colo do Útero/patologia , Displasia do Colo do Útero/virologiaRESUMO
Despite optimal diagnosis and early therapeutic interventions, the prognosis for ovarian cancer patients remains dismal because the efficacy of chemotherapy is limited by the development of resistance and off-site toxicity. Berry bioactives indicate preventive and therapeutic activities against various cancer types. Here, we examined the antiproliferative activity of berry anthocyanidins (Anthos) against drug-sensitive (A2780) and drug-resistant (A2780/CP70, OVCA432 and OVCA433) ovarian cancer cells. These drug-resistant ovarian cancer cell lines overexpress p-glycoproteins (PgP) and show >100-fold resistance to the chemotherapeutic drug cisplatin compared to A2780. We observed a dose-dependent growth inhibition of ovarian cancer cells with the Anthos. Furthermore, the treatment of drug-resistant ovarian cancer (OVCA433) cells with cisplatin in combination with the Anthos (75 µM) resulted in significantly higher cell killing. The cisplatin dose required to achieve this effect was 10 to 15-fold lower than the IC50 of cisplatin alone. However, many plant bioactives including Anthos face the challenge of poor oral bioavailability and stability. Recently, we have developed strategies to overcome these limitations by delivering Anthos via milk-derived exosomes. The exosomal Anthos (ExoAnthos) significantly enhanced the antiproliferative activity against the growth of ovarian cancer cells and inhibited tumor growth more efficiently compared to Anthos alone and a vehicle control. Often patients with cisplatin-resistant tumors retain sensitivity to paclitaxel (PAC). We prepared exosomal formulations of PAC (ExoPAC) for oral delivery as the systemic administration of PAC has severe side effects. ExoPAC delivered orally showed the same therapeutic efficacy as the free PAC delivered intraperitoneally. Finally, we report that the combination of the Anthos and PAC decreased the PgP level in a dose-dependent manner in OVCA432 cells. A significantly enhanced antitumor activity was observed with the combination of ExoPAC and ExoAnthos against A2780 tumor xenografts. Together, our data indicate that the berry Anthos are highly effective against ovarian cancer and that the milk exosomes serve as an excellent nano-carrier to enhance the drug's oral bioavailability for the management of ovarian cancer.
Assuntos
Antocianinas/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Neoplasias Ovarianas/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Animais , Antocianinas/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Portadores de Fármacos/química , Exossomos/química , Feminino , Frutas/química , Humanos , Camundongos , Camundongos Nus , Neoplasias Ovarianas/fisiopatologia , Extratos Vegetais/químicaRESUMO
Scientific evidence suggests that many herbs and spices have medicinal properties that alleviate symptoms or prevent disease. In this study, we examined the chemopreventive effects of the Apiaceae spices, anise, caraway, and celery seeds against 17ß-estrogen (E2)-mediated mammary tumorigenesis in an ACI (August-Copenhagen Irish) rat model. Female ACI rats were given either control diet (AIN 93M) or diet supplemented with 7.5% (w/w) of anise, caraway, or celery seed powder. Two weeks later, one half of the animals in each group received subcutaneous silastic implants of E2. Diet intake and body weight were recorded weekly, and animals were euthanized after 3 and 12 weeks. E2-treatment showed significantly (2.1- and 3.4-fold) enhanced growth of pituitary gland at 3 and 12 weeks, respectively. All test spices significantly offset the pituitary growth by 12 weeks, except celery which was effective as early as three weeks. Immunohistochemical analysis for proliferative cell nuclear antigen (PCNA) in mammary tissues showed significant reduction in E2-mediated mammary cell proliferation. Test spices reduced the circulating levels of both E2 and prolactin at three weeks. This protection was more pronounced at 12 weeks, with celery eliciting the highest effect. RT-PCR and western blot analysis were performed to determine the potential molecular targets of the spices. Anise and caraway diets significantly offset estrogen-mediated overexpression of both cyclin D1 and estrogen receptor α (ERα). The effect of anise was modest. Likewise, expression of CYP1B1 and CYP1A1 was inhibited by all test spices. Based on short-term molecular markers, caraway was selected over other spices based on its enhanced effect on estrogen-associated pathway. Therefore, a tumor-end point study in ACI rats was conducted with dietary caraway. Tumor palpation from 12 weeks onwards revealed tumor latency of 29 days in caraway-treated animals compared with first tumor appearance at 92 days in control group. At the end of the study (25 weeks), the tumor incidence was 96% in the control group compared with only 70% in the caraway group. A significant reduction in tumor volume (661 ± 123 vs. 313 ± 81 mm³) and tumor multiplicity (4.2 ± 0.4 vs. 2.5 ± 0.5 tumors/animal) was also observed in the caraway group compared with the control group. Together, our data show dietary caraway can significantly delay and prevent the hormonal mammary tumorigenesis by modulating different cellular and molecular targets.
Assuntos
Apiaceae/química , Transformação Celular Neoplásica/efeitos dos fármacos , Quimioprevenção , Suplementos Nutricionais , Neoplasias Mamárias Experimentais/patologia , Neoplasias Mamárias Experimentais/prevenção & controle , Especiarias , Animais , Biomarcadores , Peso Corporal , Proliferação de Células/efeitos dos fármacos , Estradiol/efeitos adversos , Estrogênios/sangue , Feminino , Neoplasias Mamárias Experimentais/sangue , Prolactina/sangue , Ratos , Carga TumoralRESUMO
Fruits, vegetables and medicinal herbs rich in phenolics antioxidants contribute toward reduced risk of age-related diseases and cancer. In this study, Psidium guajava leaf extract was fractionated in various organic solvents viz. petroleum ether, benzene, ethyl acetate, ethanl and methanol and tested for their antioxidant and antimutagenic properties. Methanolic fraction showed maximum antioxidant activity comparable to ascorbic acid and butylated hydroxyl toluene (BHT) as tested by DPPH free radical scavenging, phosphomolybdenum, FRAP (Fe3 + reducing power) and CUPRAC (cupric ions (Cu2+) reducing ability) assays. The fraction was analyzed for antimutagenic activities against sodium azide (NaN3), methylmethane sulfonate (MMS), 2-aminofluorene (2AF) and benzo(a)pyrene (BP) in Ames Salmonella tester strains. The methanol extracted fraction at 80 µg/ml concentration inhibited above 70% mutagenicity. Further, phytochemical analysis of methanol fraction that was found to be most active revealed the presence of nine major compounds by gas chromatography-mass spectrometry (GC-MS). This data suggests that guava contains high amount of phenolics responsible for broad-spectrum antimutagenic and antioxidant properties in vitro and could be potential candidates to be explored as modern phytomedicine.
Assuntos
Antimutagênicos/farmacologia , Antioxidantes/farmacologia , Mutação/efeitos dos fármacos , Extratos Vegetais/farmacologia , Folhas de Planta/química , Psidium/química , Antimutagênicos/química , Antimutagênicos/isolamento & purificação , Antioxidantes/química , Antioxidantes/isolamento & purificação , Compostos de Bifenilo/química , Cobre/química , DNA Bacteriano/efeitos dos fármacos , DNA Bacteriano/genética , Relação Dose-Resposta a Droga , Ferricianetos/química , Cromatografia Gasosa-Espectrometria de Massas , Molibdênio/química , Testes de Mutagenicidade , Mutagênicos/toxicidade , Oxirredução , Fenóis/isolamento & purificação , Fenóis/farmacologia , Fitoterapia , Picratos/química , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Plantas Medicinais , Salmonella/efeitos dos fármacos , Salmonella/genética , Solventes/químicaRESUMO
SCOPE: Syzygium cumini (jamun) is perhaps the only berry that has the diversity of anthocyanidins of blueberry and bilberry and the abundance of ellagitannins/ellagic acid of black raspberry. Here, we report the potential of jamun against 17ß-estrogen-mediated breast cancer and the role of miRNAs and other targets in disease inhibition. METHODS AND RESULTS: Female August-Copenhagen Irish rats were given AIN-93M diet or diet supplemented with jamun. Two weeks later, animals received 17ß-estradiol and were palpated weekly for the mammary tumors. At the end of 26 weeks, the jamun-diet significantly delayed the first tumor appearance by 21 days, and reduced the tumor incidence (65% versus 96%), tumor burden (313 ± 95 versus 661 ± 123 mm(3) ) and tumor multiplicity (1.8 ± 0.3 versus 4.2 ± 0.4 tumors/rat) compared to control. The experimental diet significantly reduced the estrogen-associated growth of pituitary prolactinomas, circulating prolactin and estradiol levels and offset estrogen-associated increases in mammary cell-proliferation, estrogen receptor-alpha (ER-α), and cyclinD1. miRNAs that were either overexpressed (miR-182 and miR-375) or underexpressed (miR-127 and miR-206) following estrogen-treatment were significantly protected by jamun diet. CONCLUSIONS: Together, our data show that jamun significantly offset estrogen-mediated alterations in mammary cell-proliferation, ER-α, cyclinD1, and candidate miRNAs, and that the modulation of these biomarkers correlated with a reduction in mammary carcinogenicity.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/prevenção & controle , Dieta , Preparações de Plantas/farmacologia , Syzygium/química , Animais , Antocianinas/farmacologia , Proliferação de Células/efeitos dos fármacos , Ciclina D1/genética , Ciclina D1/metabolismo , Ácido Elágico/farmacologia , Estradiol/toxicidade , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Frutas/química , Regulação Neoplásica da Expressão Gênica , Taninos Hidrolisáveis/farmacologia , Neoplasias Mamárias Experimentais , MicroRNAs/genética , MicroRNAs/metabolismo , Ratos , Ratos EndogâmicosRESUMO
Spices are used worldwide, particularly in the Asian and Middle Eastern countries, and considered protective against degenerative diseases, including cancer. Here, we report the efficacy of aqueous and non-aqueous extracts of 11 Apiaceae spices for free radical-scavenging activity and to inhibit cytochrome P450s in two separate reactions involving: 1) 4-hydroxy-17ß-estradiol (4E2), DNA, and CuCl2 and 2) 17ß-estradiol, rat liver microsomes, cofactors, DNA and CuCl2. Oxidative DNA adducts resulting from redox cycling of 4E2 were analyzed by (32)P-postlabeling. Aqueous (5 mg/ml) and non-aqueous extracts (6 mg/ml) substantially inhibited (83-98%) formation of DNA adducts in the microsomal reaction. However, in nonmicrosomal reaction, only aqueous extracts showed the inhibitory activity (83-96%). Adduct inhibition was also observed at five-fold lower concentrations of aqueous extracts of cumin (60%) and caraway (90%), and 10-fold lower concentrations of carrot seeds (76%) and ajowan (90%). These results suggests the presence of 2 groups of phytochemicals: polar compounds that have free radical-scavenging activity and lipophilic compounds that selectively inhibit P450 activity associated with estrogen metabolism. Because most of these Apiaceae spices are used widely with no known toxicity, the phytochemicals from the Apiaceae spices used in foods may be potentially protective against estrogen-mediated breast cancer.
Assuntos
Antioxidantes/farmacologia , Apiaceae/química , Extratos Vegetais/farmacologia , Especiarias , Animais , Inibidores das Enzimas do Citocromo P-450/farmacologia , Adutos de DNA , Dano ao DNA/efeitos dos fármacos , Estradiol/metabolismo , Estrogênios de Catecol/metabolismo , Estrogênios de Catecol/farmacocinética , Sequestradores de Radicais Livres/farmacologia , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Extratos Vegetais/química , Ratos , Testículo/efeitos dos fármacos , Testículo/metabolismoRESUMO
Human papilloma virus (HPV) is the well-established etiological factor of cervical cancer. E6 and E7 oncoproteins expressed by HPV are known to inactivate tumor suppressor proteins p53 and pRb, respectively. Tanshinone IIA (Tan IIA) is a diterpenoid naphthoquinone found in the traditional Chinese medicine Danshen (Salvia sp.). Tan IIA has been shown to possess anti-tumor activity against several cancer types. In this study we show that Tan IIA potently inhibited proliferation of the human cervical cancer CaSki, SiHa, HeLa and C33a cells. Mechanistically in HPV positive CaSki cells, Tan IIA was found to (i) downregulate expression of HPV E6 and E7 genes and modulate associated proteins E6AP and E2F1, (ii) cause S phase cell cycle arrest, (iii) induce accumulation of p53 and alter expression of p53-dependent targets, (iv) modulate pRb and related proteins, and (v) cause p53-mediated apoptosis by moderating Bcl2, Bax, caspase-3, and PARP cleavage expressions. In vivo, Tan IIA resulted in over 66% reduction in tumor volume of cervical cancer xenograft in athymic nude mice. Tan IIA treated tumor tissues had lower expression of proliferation marker PCNA and changes in apoptosis targets were in agreement with in vitro studies, further confirming reduced proliferation and involvement of multiple targets behind anti-cancer effects. This is the first demonstration of Tan IIA to possess significant anti-viral activity by repressing HPV oncogenes leading to inhibition of cervical cancer. Together, our data suggest that Tan IIA can be exploited as a potent therapeutic agent for the prevention and treatment of cervical and other HPV-related cancers.
Assuntos
Abietanos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Proteínas Oncogênicas Virais/metabolismo , Proteínas E7 de Papillomavirus/metabolismo , Proteínas Repressoras/metabolismo , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/patologia , Animais , Western Blotting , Ciclo Celular , Proliferação de Células , Feminino , Citometria de Fluxo , Humanos , Técnicas Imunoenzimáticas , Camundongos , Camundongos Nus , Proteínas Oncogênicas Virais/genética , Papillomaviridae/genética , Papillomaviridae/isolamento & purificação , Proteínas E7 de Papillomavirus/genética , Infecções por Papillomavirus/tratamento farmacológico , Infecções por Papillomavirus/metabolismo , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/virologia , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Proteínas Repressoras/genética , Proteína do Retinoblastoma/genética , Proteína do Retinoblastoma/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/virologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Punicalagin (PC) is an ellagitannin found in the fruit peel of Punica granatum. We have demonstrated antioxidant and antigenotoxic properties of Punica granatum and showed that PC and ellagic acid (EA) are its major constituents. In this study, we demonstrate the antimutagenic potential, inhibition of BP-induced DNA damage, and antiproliferative activity of PC and EA. Incubation of BP with rat liver microsomes, appropriate cofactors, and DNA in the presence of vehicle or PC and EA showed significant inhibition of the resultant DNA adducts, with essentially complete inhibition (97%) at 40 µ M by PC and 77% inhibition by EA. Antimutagenicity was tested by Ames test. PC and EA dose-dependently and markedly antagonized the effect of tested mutagens, sodium azide, methyl methanesulfonate, benzo[a]pyrene, and 2-aminoflourine, with maximum inhibition of mutagenicity up to 90 percent. Almost all the doses tested (50-500 µ M) exhibited significant antimutagenicity. A profound antiproliferative effect on human lung cancer cells was also shown with PC and EA. Together, our data show that PC and EA are pomegranate bioactives responsible for inhibition of BP-induced DNA adducts and strong antimutagenic, antiproliferative activities. However, these compounds are to be evaluated in suitable animal model to assess their therapeutic efficacy against cancer.
Assuntos
Adutos de DNA/efeitos dos fármacos , Ácido Elágico/administração & dosagem , Taninos Hidrolisáveis/administração & dosagem , Extratos Vegetais/administração & dosagem , Animais , Antioxidantes/administração & dosagem , Benzo(a)pireno/farmacologia , Dano ao DNA/efeitos dos fármacos , Ácido Elágico/química , Humanos , Taninos Hidrolisáveis/química , Lythraceae/química , Mutagênese/efeitos dos fármacos , Extratos Vegetais/química , Ratos , Salmonella typhimurium/efeitos dos fármacosRESUMO
Dietary polyphenols may contribute to the prevention of several degenerative diseases, including cancer. Anthocyanins have been shown to possess potential anticancer activity. The aim of this study was to determine anthocyanin bioavailability in lung tissue of mice fed a blueberry diet (5% w/w) for 10 days or a bolus dose (10 mg/mouse; po) of a native mixture of bilberry anthocyanidins. All five anthocyanidins present in the blueberry were detected in the lung tissue using improved methods. The effect of various solvents on the stability of anthocyanins and their recovery from the biomatrix was analyzed. Detection of anthocyanins and their metabolites was performed by UPLC and LC-MS. Although anthocyanins were not detected, cyanidin was detected by UPLC-PDA and other anthocyanidins were detected by LC-MS, following conversion to anthocyanidins and selective extraction in isoamyl alcohol. The results show that anthocyanins can be detected in lung tissue of blueberry-fed mice and thus are bioavailable beyond the gastrointestinal tract.
Assuntos
Antocianinas/análise , Mirtilos Azuis (Planta)/metabolismo , Pulmão/química , Extratos Vegetais/análise , Animais , Antocianinas/metabolismo , Cromatografia Líquida de Alta Pressão , Feminino , Pulmão/metabolismo , Espectrometria de Massas , Camundongos , Camundongos Nus , Extratos Vegetais/metabolismoRESUMO
Polymeric implants (millirods) have been tested for local delivery of chemotherapeutic agents in cancer treatment. Modeling of drug release profiles is critical as it may provide theoretical insights on rational implant design. In this study, a biodegradable poly (ε-caprolactone) (PCL) polymeric implant delivery system was tested to deliver green tea polyphenols (GTPs), both in vitro and in vivo. Factors including polymer compositions, supplements, drug loads, and surface area of implants were investigated. Our data showed that GTPs were released from PCL implants continuously for long durations, and drug load was the main determining factor of GTPs release. Furthermore, rates of in vitro release and in vivo release in the rat model followed similar kinetics for up to 16 months. A mathematical model was deduced and discussed. GTP implants have the potential to be used systemically and locally at the tumor site as an alternative strategy.
Assuntos
Antioxidantes/administração & dosagem , Plásticos Biodegradáveis/química , Camellia sinensis/química , Caproatos/química , Lactonas/química , Extratos Vegetais/administração & dosagem , Folhas de Planta/química , Polifenóis/administração & dosagem , Animais , Anticarcinógenos/administração & dosagem , Anticarcinógenos/química , Anticarcinógenos/metabolismo , Anticarcinógenos/farmacocinética , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/metabolismo , Antineoplásicos Fitogênicos/farmacocinética , Antioxidantes/química , Antioxidantes/metabolismo , Antioxidantes/farmacocinética , Plásticos Biodegradáveis/metabolismo , Caproatos/metabolismo , Catequina/administração & dosagem , Catequina/análogos & derivados , Catequina/química , Catequina/metabolismo , Catequina/farmacocinética , Cromanos/administração & dosagem , Cromanos/química , Cromanos/metabolismo , Ciclodextrinas/química , Ciclodextrinas/metabolismo , Composição de Medicamentos , Implantes de Medicamento , Feminino , Lactonas/metabolismo , Peso Molecular , Extratos Vegetais/química , Extratos Vegetais/metabolismo , Extratos Vegetais/farmacocinética , Polietilenoglicóis/química , Polietilenoglicóis/metabolismo , Polifenóis/química , Polifenóis/metabolismo , Polifenóis/farmacocinética , Propilenoglicóis/química , Propilenoglicóis/metabolismo , Ratos , Ratos Endogâmicos ACI , Solubilidade , Propriedades de Superfície , Temperatura de TransiçãoRESUMO
Berries are gaining increasing importance lately for their chemopreventive and therapeutic potential against several cancers. In earlier studies, a blueberry-supplemented diet has shown protection against 17ß-estradiol (E2)-mediated mammary tumorigenesis. This study tested both preventive and therapeutic activities of diet supplemented with whole blueberry powder (50:50 blend of Tifblue and Rubel). Animals received 5% blueberry diet, either 2 weeks prior to or 12 weeks after E2 treatment in preventive and therapeutic groups, respectively. Both interventions delayed the tumor latency for palpable mammary tumors by 28 and 37 days, respectively. Tumor volume and multiplicity were also reduced significantly in both modes. The effect on mammary tumorigenesis was largely due to down-regulation of CYP 1A1 and ER-α gene expression and also favorable modulation of microRNA (miR-18a and miR-34c) levels. These data suggest that the blueberry blend tested is effective in inhibiting E2-mediated mammary tumorigenesis in both preventive and therapeutic modes.
Assuntos
Mirtilos Azuis (Planta)/metabolismo , Neoplasias da Mama/dietoterapia , Estradiol/metabolismo , Estrogênios/metabolismo , Frutas/metabolismo , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/prevenção & controle , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Ratos , Ratos Endogâmicos ACIRESUMO
It is well known that the intake of antioxidants with increased consumption of fruits and vegetables and medicinal herbs contributes towards reduced risk of certain diseases including cancers. This study aims to evaluate the broad-spectrum antioxidant and antimutagenic activities as well as to elucidate phytochemical profile of an Indian medicinal plant Murraya koenigii (curry) leaves. Leaves of the plant were successively fractionated in various organic solvents. Benzene fraction demonstrated the highest phenolic content followed by petroleum ether. The benzene fraction showed maximum antioxidant activity in all tested assays, namely, phosphomolybdenum, 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical, ferric reducing antioxidant power (FRAP) and cupric reducing antioxidant capacity (CUPRAC) assays. Based on the promising broad-spectrum antioxidant activity, benzene fraction was further evaluated for antimutagenic activity and showed a dose-dependent antimutagenic response in Ames Salmonella mutagenicity assay. It inhibited 72-86% mutagenicity induced by sodium azide, methyl methanesulfonate, benzo(a)pyrene, and 2-aminoflourene at the maximum tested concentration (100 µg/mL) in Salmonella typhimurium tester strains. At least 21 compounds were detected by GC/MS. The findings clearly demonstrated that phenolic-rich benzene fraction has promising broad-spectrum antioxidant and antimutagenic property and needs further evaluation to exploit its therapeutic potential.
Assuntos
Antimutagênicos/farmacologia , Antioxidantes/farmacologia , Murraya/química , Extratos Vegetais/farmacologia , Compostos de Bifenilo/metabolismo , Fracionamento Químico , Sequestradores de Radicais Livres/farmacologia , Cromatografia Gasosa-Espectrometria de Massas , Testes de Mutagenicidade , Oxirredução/efeitos dos fármacos , Picratos/metabolismo , Folhas de Planta/químicaRESUMO
INTRODUCTION: Quantitative analysis and standardisation of plant extracts or herbal products is a tedious process requiring time-consuming sample preparation and analytical method development for the resolution of analyte peaks from the complex natural extract. Quantitative analysis by HPLC requires a pure authentic standard of the compound being quantified. We report here a quantitative NMR (qNMR) method for quantitative analysis of three medicinal plant extracts and their herbal products without the need of authentic standards. Quantitation can be done by using any commercially available pure sample as an internal reference standard. OBJECTIVE: To develop a reliable method for standardisation and quantitative analysis of extracts from medicinal plants Eugenia jambolana, Withania somnifera and Aegle marmelos and their herbal products using qNMR. METHODOLOGY: The (1) H-NMR spectra of known amounts of crude plant extracts with internal standards were recorded in deuterated solvents and quantitation was performed by calculating the relative ratio of the peak area of selected proton signals of the target compounds and the internal reference standard. Anthocyanins [delphinidin-3,5-diglucoside (1), petunidin-3,5-diglucoside (2) and malvidin-3,5-diglucoside (3)] for E. jambolana fruit extract and imperatorin (4) for A. marmelos fruit extract were selected as marker constituents for quantitation and 1,3,5-trimethoxybenzene (TMB) was used as an internal reference standard. Total withanolide content was determined for W. somnifera using 2,4-diformyl phloroglucinol as an internal reference standard. RESULTS: The (1) H-NMR gave a linear response for the marker constituents, anthocyanins, withaferin A and imperatorin. Using the described method, the amount of anthocyanins in Amberlite(R) XAD7HP and Sephadex enriched extracts of E. jambolana was 3.77% and 9.57% (delphinidin-3,5-diglucoside), 4.72% and 12.0% (petunidin-3,5-diglucoside), 6.55% and 15.70% (malvidin-3,5-diglucoside), respectively. The imperatorin content was 0.424% in A. marmelos fruit and 0.090 % and 0.114% in sharbat and candies. Total withanolides content was 0.191% in the chloroform extract and 0.234% in the capsule extract. These values are in accordance with HPLC results. CONCLUSION: This qNMR technique could be used for NMR fingerprinting and quantitation for the purpose of quality control and standardisation of many plant-based herbal products and medicines and has certain advantages over HPLC.
Assuntos
Espectroscopia de Ressonância Magnética/métodos , Extratos Vegetais/química , Preparações de Plantas/química , Plantas Medicinais/química , Aegle/química , Antocianinas/análise , Doces/análise , Frutas/química , Espectroscopia de Ressonância Magnética/normas , Extratos Vegetais/análise , Padrões de Referência , Reprodutibilidade dos Testes , Syzygium/química , Withania/química , Vitanolídeos/análiseRESUMO
We previously demonstrated the protective effects of blueberry (BB) and black raspberry (BRB) supplemented at 2.5% dose in an ACI rat mammary tumor model. Here, we assessed a dose-related alteration in tumor indices with diet supplemented with 5% BB or BRB powder. The diet was well tolerated. Tumor palpation from 12 weeks revealed first tumor appearance by 84 days in the control group, that was delayed by 24 and 39 days with the BB and BRB diets, respectively (p = 0.04). Ellagic acid detected in the plasma of rats fed the BRB diet was in the range of 96.6-294.2 ng/mL. While the BB diet showed better efficacy in reducing mammary tissue proliferation and tumor burden, tumor latency was delayed efficiently by BRB. Furthermore, BB was effective in downregulating CYP1A1 expression, while BRB downregulated ERα expression effectively. Distinct anticarcinogenic effects of the two berries correspond to their distinct phytochemical signatures.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Mirtilos Azuis (Planta)/química , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Regulação para Baixo/efeitos dos fármacos , Estrogênios/metabolismo , Extratos Vegetais/administração & dosagem , Rosaceae/química , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Transformação Celular Neoplásica/efeitos dos fármacos , Estrogênios/genética , Feminino , Frutas/química , Humanos , Ratos , Ratos Endogâmicos ACIRESUMO
Colored fruits, particularly berries, are highly chemoprotective because of their antioxidant, antiproliferative, and antiinflammatory activities. We report the cancer chemoprotective potential of Syzygium cumini L., commonly known as jamun or Indian blackberry. Anthocyanins and other polyphenolics were extracted with acidic ethanol and enriched by amberlite XAD7/HP20 (1:1). The pulp powder was found to contain 0.54% anthocyanins, 0.17% ellagic acid/ellagitannins, and 1.15% total polyphenolics. Jamun seed contained no detectable anthocyanins but had higher amounts of ellagic acid/ellagitannins (0.5%) and total polyphenolics (2.7%) than the pulp powder. Upon acid hydrolysis, the pulp extract yielded 5 anthocyanidins by HPLC: malvidin (44.4%), petunidin (24.2%), delphinidin (20.3%), cyanidin (6.6%), and peonidin (2.2%). Extracts of both jamun pulp (1,445 ± 64 µmol of trolox equivalent (TE)/g) and seeds (3,379 ± 151 µM of TE/g) showed high oxygen radical absorbance capacity. Their high antioxidant potential was also reflected by 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid)- and 2,2-diphenyl-1-picrylhydrazyl-scavenging and ferrous ion-chelating activities. We also analyzed antiproliferative activity of jamun extracts against human lung cancer A549 cells. The hydrolyzed pulp and seed extracts showed significant antiproliferative activity. However, unhydrolyzed extracts showed much less activity. These data showed that in addition to 5 anthocyanidins, jamun contains appreciable amounts of ellagic acid/ellagitannins, with high antioxidant and antiproliferative activities.
Assuntos
Antocianinas/farmacologia , Antioxidantes/farmacologia , Proliferação de Células/efeitos dos fármacos , Taninos Hidrolisáveis/farmacologia , Extratos Vegetais/farmacologia , Syzygium/química , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Frutas/química , Humanos , Sementes/químicaRESUMO
Multidrug resistance (MDR) in microorganisms is a cause of major concern for clinicians and pharmaceutical industries. Continuous development of new antimicrobial drugs with multiple targets and potentials is expected to efficiently combat MDR in these microorganisms. In a continued exploration of new antimicrobial drug leads, 11 marine natural products, semisynthetic, or related synthetic analogs (1-11) and two tobacco cembranoids (12 and 13) were screened for their antimicrobial, antioxidant, and antimutagenic activities. Eight compounds showed varying levels of both antibacterial and antifungal activities. Compounds such as 17-O-methyllatrunculin-A, verongiaquinol, (1S,2E,4R,6R,7E,11E)-2,7,11-cembratriene-4,6-diol), and manzamine-A showed a broad spectrum of activity, inhibiting six of seven tested bacteria with zone of inhibition diameter from 9 to 30 mm. Four of these active compounds also showed antifungal activity. The findings of the in vitro time-kill assay of the most active compound, verongiaquinol, against Staphylococcus aureus indicated its subinhibitory effect at the level lower than the minimal inhibitory concentration (MIC) values (i.e., 2 and 4 µg/mL). At the MIC (8 µg/mL), bacterial cells were completely killed within 18 hours of incubation. DPPH free radical scavenging activity was demonstrated by five compounds in the range of 89.65-36.19% decolorization. Further, four compounds evaluated for their antimutagenic activity against the directly acting mutagens, methyl methanesulfonate and sodium azide, in Salmonella typhimurium strains, interestingly, showed no sign of mutagenicity. Verongiaquinol and manzamine A, in fact, reduced the mutagenicity by 50-75% at a dose of 5 µg/plate in different test strains. Our study seems to provide some novel antimicrobial leads with strong antioxidant potential and the associated ability of antimutagenicity.