ABSTRACT
The chemical warfare agent sulfur mustard and its structural analog nitrogen mustard (NM) cause severe vesicating skin injuries. The pathologic mechanisms for the skin injury following mustard exposure are poorly understood; therefore, no effective countermeasure is available. Previous reports demonstrated the protective activity of carvedilol, a US Food and Drug Administration (FDA)-approved ß-blocker, against UV radiation-induced skin damage. Thus, the current study evaluated the effects of carvedilol on NM-induced skin injuries in vitro and in vivo. In the murine epidermal cell line JB6 Cl 41-5a, ß-blockers with different receptor subtype selectivity were examined. Carvedilol and both of its enantiomers, R- and S-carvedilol, were the only tested ligands statistically reducing NM-induced cytotoxicity. Carvedilol also reduced NM-induced apoptosis and p53 expression. In SKH-1 mice, NM increased epidermal thickness, damaged skin architecture, and induced nuclear factor κB (NF-κB)-related proinflammatory genes as assessed by RT2 Profiler PCR (polymerase chain reaction) Arrays. To model chemical warfare scenario, 30 minutes after exposure to NM, 10 µM carvedilol was applied topically. Twenty-four hours after NM exposure, carvedilol attenuated NM-induced epidermal thickening, Ki-67 expression, a marker of cellular proliferation, and multiple proinflammatory genes. Supporting the in vitro data, the non-ß-blocking R-enantiomer of carvedilol had similar effects as racemic carvedilol, and there was no difference between carvedilol and R-carvedilol in the PCR array data, suggesting that the skin protective effects are independent of the ß-adrenergic receptors. These data suggest that the ß-blocker carvedilol and its enantiomers can be repurposed as countermeasures against mustard-induced skin injuries. SIGNIFICANCE STATEMENT: The chemical warfare agent sulfur mustard and its structural analog nitrogen mustard cause severe vesicating skin injuries for which no effective countermeasure is available. This study evaluated the effects of US Food and Drug Administration (FDA)-approved ß-blocker carvedilol on nitrogen mustard-induced skin injuries to repurpose this cardiovascular drug as a medical countermeasure.
Subject(s)
Chemical Warfare Agents , Mustard Gas , Animals , Mice , Mechlorethamine/toxicity , Mechlorethamine/metabolism , Carvedilol/pharmacology , Carvedilol/therapeutic use , Carvedilol/metabolism , Chemical Warfare Agents/toxicity , Mustard Gas/pharmacology , Mustard Gas/toxicity , Skin , Adrenergic beta-Antagonists/pharmacologyABSTRACT
The objective of this study was to develop proliposomal formulations for a poorly bioavailable drug, aliskiren hemifumarate (AKH). A solvent evaporation method was used to prepare proliposomes using different lipids. The lipids of selection were soy phosphatidylcholine (SPC), dimyristoylphosphatidylcholine (DMPC), and dimyristoylphosphatidylglycerol sodium (DMPG Na), stearylamine, and cholesterol in various ratios. Proliposomes were evaluated for particle size, zeta potential, in vitro drug release, in vitro permeability, and in vivo pharmacokinetics upon hydration with aqueous phase. In vitro drug release studies were conducted in 0.01 N hydrochloric acid using USP type II dissolution apparatus. Parallel artificial membrane permeation assay (PAMPA) and Caco-2 cell line models were used to study the in vitro drug permeation. Male Sprague-Dawley (SD) rats were used to conduct in vivo pharmacokinetic studies. Among different formulations, proliposomes with drug/DMPC/cholesterol/stearylamine in the ratio of 1:5:0.025:0.050 (w/w/w/w) demonstrated the desired particle size, higher zeta potential, and higher encapsulation efficiency. The PAMPA and Caco-2 cell line experiments showed a significantly higher permeability of AKH with proliposomes as compared to pure AKH. In animal studies, the optimized formulation of proliposomes showed significant improvement in the rate and extent of absorption of AKH. Specifically, following a single oral administration, the relative bioavailability of AKH proliposome formulation was 230% when compared to pure AKH suspension.
Subject(s)
Drug Carriers , Liposomes , Administration, Oral , Amides , Animals , Biological Availability , Caco-2 Cells , Cholesterol , Dimyristoylphosphatidylcholine , Drug Carriers/pharmacokinetics , Drug Liberation , Fumarates , Humans , Liposomes/pharmacokinetics , Male , Particle Size , Permeability , Rats , Rats, Sprague-DawleyABSTRACT
Streptomycin was the first discovered aminoglycoside antibiotic. It has been widely applied in veterinary medicine for the prevention and treatment of bacterial infection. However, the current detection methods are not satisfactory in terms of sensitivity and sample process, which makes them unsuitable for a pharmacokinetic study. A high-performance liquid chromatography-mass spectrometric method employing positive electrospray ionization was developed and validated for the determination of streptomycin concentration in mice plasma. A simple protein precipitation method was utilized to extract streptomycin as well as the internal standard (kanamycin) from mouse plasma. This assay method was validated in terms of specificity, sensitivity, precision, accuracy and recovery. This method was applied to a pharmacokinetic study in mice following intramuscular administration of 200 mg/kg streptomycin. The lower limit of quantification of the developed assay method for streptomycin was 10 ng/mL. The intra-day and inter-day precision was evaluated with the coefficient of variations <14.3%, whereas the mean accuracy ranged from 87.0 to 105.0%. The samples were stable under the experimental conditions. The present method provides a robust, fast and sensitive analytical approach for the quantification of streptomycin in mouse plasma and has been successfully applied to a pharmacokinetic study in mice.
Subject(s)
Chromatography, High Pressure Liquid/methods , Streptomycin/blood , Streptomycin/pharmacokinetics , Tandem Mass Spectrometry/methods , Animals , Drug Stability , Linear Models , Mice , Reproducibility of Results , Sensitivity and Specificity , Streptomycin/chemistryABSTRACT
The objective of the present study was to develop a proliposomal formulation to increase the oral bioavailability of dronedarone hydrochloride (dronedarone HCl) by enhancing solubility, dissolution, and/or intestinal absorption. Proliposomes were prepared by using solvent evaporation method. In this process, different ratios of drug, phospholipids, such as soy phosphatidylcholine (SPC), Phospholipon 90H, hydrogenated egg phosphatidylcholine (HEPC), and dimyristoyl phosphatidylglycerol (DMPG), and cholesterol were used. Physical characterization and in vitro dissolution studies were evaluated for the prepared formulations. In vitro transport across the membrane was carried out using Caco-2 cells. Among all the formulations, the amount of drug released in dissolution was higher with DPF8 formulation (drug:DMPG Na:cholesterol:::1:2:0.2) compared to the pure drug. Also, Caco-2 cell permeability studies resulted in 2.6-fold increase in apparent permeability. Optimized formulation was evaluated in vivo in male Sprague-Dawley rats. After single oral administration of optimized formulation (DPF8), a relative bioavailability of 148.36% was achieved compared to the pure drug. Improved oral bioavailability of dronedarone could be provided by an optimized proliposomal formulation with enhanced solubility, permeability, and oral absorption.
Subject(s)
Anti-Arrhythmia Agents/chemistry , Dronedarone/chemistry , Liposomes , Administration, Oral , Animals , Anti-Arrhythmia Agents/administration & dosage , Anti-Arrhythmia Agents/pharmacokinetics , Biological Availability , Caco-2 Cells , Cholesterol , Dronedarone/administration & dosage , Dronedarone/pharmacokinetics , Drug Carriers , Drug Compounding , Humans , Male , Particle Size , Permeability , Phospholipids , Rats , Rats, Sprague-Dawley , SolubilityABSTRACT
Recent studies suggest that the ß-blocker drug carvedilol prevents skin carcinogenesis but the mechanism is unknown. Carvedilol is one of a few ß-blockers identified as biased agonist based on an ability to promote ß-arrestin-mediated processes such as ERK phosphorylation. To understand the role of phosphoproteomic signaling in carvedilol's anticancer activity, the mouse epidermal JB6 P+ cells treated with EGF, carvedilol, or their combination were analyzed using the Phospho Explorer Antibody Array containing 1318 site-specific and phospho-specific antibodies of over 30 signaling pathways. The array data indicated that both EGF and carvedilol increased phosphorylation of ERK's cytosolic target P70S6 K while its nuclear target ELK-1 were activated only by EGF; Furthermore, EGF-induced phosphorylation of ELK-1 and c-Jun was attenuated by carvedilol. Subcellular fractionation analysis indicated that ERK nuclear translocation induced by EGF was blocked by co-treatment with carvedilol. Western blot and luciferase reporter assays confirmed that the biased ß-blockers carvedilol and alprenolol blocked EGF-induced phosphorylation and activation of c-Jun/AP-1 and ELK-1. Consistently, both carvedilol and alprenolol strongly prevented EGF-induced neoplastic transformation of JB6 P+ cells. Remarkably, oral carvedilol treatment significantly inhibited the growth of A375 melanoma xenograft in SCID mice. As nuclear translocation of ERK is a key step in carcinogenesis, inhibition of this event is proposed as a novel anticancer mechanism for biased ß-blockers such as carvedilol.
Subject(s)
Adrenergic beta-Antagonists/therapeutic use , Anticarcinogenic Agents/therapeutic use , Carcinogenesis/drug effects , Carvedilol/therapeutic use , Melanoma/prevention & control , Adrenergic beta-Antagonists/pharmacology , Animals , Anticarcinogenic Agents/pharmacology , Carcinogenesis/metabolism , Carcinogenesis/pathology , Carvedilol/pharmacology , Epidermal Growth Factor/metabolism , HEK293 Cells , Humans , Male , Melanoma/metabolism , Melanoma/pathology , Mice, Inbred NOD , Mice, SCID , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Phosphorylation/drug effects , Proteome/metabolism , Proto-Oncogene Proteins c-jun/metabolismABSTRACT
Ganoderma lucidum (GL), commonly known as "Lingzhi", is a well-known medicinal mushroom with antioxidant and anti-cancer activity. This study examined the effects of a commercial GL product (GLSF) containing the spore and fruiting body in a 30:8 ratio on tobacco smoke carcinogen-induced lung toxicity and carcinogenesis. The potential chemopreventive effect of GLSF was evaluated in vitro and in vivo. The non-tumorous human bronchial epithelial cells (BEAS-2B cells) were treated with GLSF extract (0.025 and 0.05 mg/mL), which significantly blocked malignant transformation induced by benzo[a]pyrene diol epoxide (BPDE) in a dose-dependent manner. To confirm its anti-carcinogenic activity in vivo, the mice were pre-treated with GLSF (2.0 g/kg of body weight) or curcumin (100 mg/kg of body weight) by oral gavage daily for 7 days and then exposed to a single dose of benzo[a]pyrene (B[a]P) (125 mg/kg of body weight). The GLSF-treated mice showed a significant reduction in B[a]P-induced lung toxicity, as indicated by decreased lactate dehydrogenase activity, malondialdehyde levels, inflammatory cell infiltration, and improved lung histopathology. We next determined the chemopreventive activity of GLSF in mice which were exposed to two weekly doses of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK, 100 mg/kg, on the 1st and 8th days) and fed with control or a modified diet containing GLSF (2.0 g/kg) or metformin (250 mg/kg) for 33 weeks. The GLSF and metformin treatments blocked NNK-induced lung tumor development by decreasing the lung weight, tumor area, and tumor burden compared to the mice exposed to NNK only. GLSF treatment also attenuated the expression of inflammatory, angiogenic, and apoptotic markers in lung tumors. Therefore, GLSF may be used for ameliorating tobacco smoke carcinogens-induced lung toxicity and carcinogenesis.
ABSTRACT
The R-carvedilol enantiomer, present in the racemic mixture of the chiral drug carvedilol, does not bind to the ß-adrenergic receptors, but exhibits skin cancer preventive activity. For skin delivery, R-carvedilol-loaded transfersomes were prepared using various ratios of drug, lipids, and surfactants, and characterized for particle size, zeta potential, encapsulation efficiency, stability, and morphology. Transfersomes were compared for in vitro drug release and ex vivo skin penetration and retention. Skin irritation was evaluated by viability assay on murine epidermal cells and reconstructed human skin culture. Single-dose and repeated-dose dermal toxicity was determined in SKH-1 hairless mice. Efficacy was evaluated in SKH-1 mice exposed to single or multiple ultraviolet (UV) radiations. Transfersomes released the drug at a slower rate, but significantly increased skin drug permeation and retention compared with the free drug. The transfersome with a drug-lipid-surfactant ratio of 1:3:0.5 (T-RCAR-3) demonstrated the highest skin drug retention and was selected for further studies. T-RCAR-3 at 100 µM did not induce skin irritation in vitro and in vivo. Topical treatment with T-RCAR-3 at 10 µM effectively attenuated acute UV-induced skin inflammation and chronic UV-induced skin carcinogenesis. This study demonstrates feasibility of using R-carvedilol transfersome for preventing UV-induced skin inflammation and cancer.
ABSTRACT
BACKGROUND/AIM: Prostate cancer is currently the second most common cancer in men and chemotherapy is the main treatment for metastatic castrate-resistant prostate cancers (mCRPC). However, chemoresistance leading to treatment failure is inevitable. Thus, therapeutic approaches that can overcome chemoresistance are important areas of research for cancer chemotherapy. MATERIALS AND METHODS: In the present study, six components of tripterygium wilfordii including celastrol, triptolide, pristimerin, triptonide, demethylzeylasteral, and wilforlide A were screened for their chemosensitizing effect on drug-resistant prostate cancer cell lines PC3 and DU145. The most active compound was further investigated on its potential mechanism of action and in vivo efficacy using a SCID mouse model. RESULTS: Among the six components only wilforlide A significantly enhanced sensitivity to docetaxel (by reducing the IC50 in resistant prostate cancer cell lines). Wilforlide A inhibited P-glycoprotein efflux transporter and downregulated cyclin E2 splice variant 1 mRNA, both have been known as mechanisms of resistance. The chemosensitizing effect was further verified using a xenograft mouse model. In the high-dose treatment group, the combination of wilforlide A and docetaxel significantly retarded tumor growth of resistant prostate cancer, although neither docetaxel nor wilforlide A monotreatment groups showed any effect. CONCLUSION: Wilforlide A was found to enhance the chemosensitizing effect of docetaxel both in vitro and in vivo. Further studies are warranted to verify wilforlide A as a new drug candidate to overcome docetaxel resistance in prostate cancer.
Subject(s)
Prostatic Neoplasms, Castration-Resistant , Taxoids , Animals , Cell Line, Tumor , Docetaxel/pharmacology , Humans , Male , Mice , Mice, SCID , Oleanolic Acid/analogs & derivatives , Pentacyclic Triterpenes , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/metabolism , Prostatic Neoplasms, Castration-Resistant/pathology , Taxoids/pharmacology , Taxoids/therapeutic useABSTRACT
The ß-blocker carvedilol prevents ultraviolet (UV)-induced skin cancer, but systemic drug administration may cause unwanted cadiovascular effects. To overcome this limitation, a topical delivery system based on transfersome (T-CAR) was characterized ex vivo and in vivo. T-CAR was visualized by Transmission Electron Microscopy as nanoparticles of spherical and unilamellar structure. T-CAR incorporated into carbopol gel and in suspension showed similar drug permeation and deposition profiles in Franz diffusion cells loaded with porcine ear skin. In mice exposed to a single dose UV, topical T-CAR gel (10⯵M) significantly reduced UV-induced skin edema and cyclobutane pyrimidine dimer formation. In mice exposed to chronic UV radiation for 25â¯weeks, topical T-CAR gel (10⯵M) significantly delayed the incidence of tumors, reduced tumor number and burden, and attenuated Ki-67 and COX-2 expression. The T-CAR gel was subsequently examined for skin deposition, systemic absorption and cardiovascular effects in mice. In mice treated with repeated doses of T-CAR gel (100⯵M), the drug was undetectable in plasma, the heart rate was unaffected, but skin deposition was significantly higher than mice treated with oral carvedilol (32â¯mg/kg/day). These data indicate that the carbopol-based T-CAR gel holds great promise for skin cancer prevention with negligible systemic effects.
Subject(s)
Pharmaceutical Preparations , Skin Neoplasms , Absorption, Physiological , Animals , Carvedilol , Mice , Skin Neoplasms/prevention & control , Swine , Ultraviolet RaysABSTRACT
Nonalcoholic fatty liver disease (NAFLD) is intricately linked to metabolic disease (including obesity, glucose intolerance, and insulin resistance) and encompasses a spectrum of disorders including steatosis, nonalcoholic steatohepatitis (NASH), and fibrosis. Rodents consuming high-fat (HF; â¼40 kcal% fat including fats containing higher concentrations of saturated and trans fats), high-fructose (HFr), and high-cholesterol (HC) diets display many clinically relevant characteristics of NASH, along with other metabolic disorders. C57BL/6 mice are the most commonly used animal model because they can develop significant metabolic disorders including severe NASH with fibrosis after months of feeding, but other models also are susceptible. The significant number of diets that contain these different factors (i.e., HF, HFr, and HC), either alone or in combination, makes the choice of diet difficult. This methodology review describes the efficacy of these nutrient manipulations on the NAFLD phenotype in mice, rats, guinea pigs, hamsters, and nonhuman primates.
ABSTRACT
The medicinal mushroom Ganoderma lucidum (GL, Reishi or Lingzhi) exhibits an inhibitory effect on cancers. However, the underlying mechanism of the antitumor activity of GL is not fully understood. In this study, we characterized the gene networks regulated by a commercial product of GL containing a mixture of spores and fruiting bodies namely "GLSF", in colorectal carcinoma. We found that in vitro co-administration of GLSF extract at non-toxic concentrations significantly potentiated growth inhibition and apoptosis induced by paclitaxel in CT26 and HCT-15 cells. GLSF inhibited NF-κB promoter activity in HEK-293 cells but did not affect the function of P-glycoprotein in K562/DOX cells. Furthermore, we found that when mice were fed a modified diet containing GLSF for 1 month prior to the CT26 tumor cell inoculation, GLSF alone or combined with Nab-paclitaxel markedly suppressed tumor growth and induced apoptosis. RNA-seq analysis of tumor tissues derived from GLSF-treated mice identified 53 differentially expressed genes compared to normal tissues. Many of the GLSF-down-regulated genes were involved in NF-κB-regulated inflammation pathways, such as IL-1ß, IL-11 and Cox-2. Pathway enrichment analysis suggested that several inflammatory pathways involving leukocyte migration and adhesion were most affected by the treatment. Upstream analysis predicted activation of multiple tumor suppressors such as α-catenin and TP53 and inhibition of critical inflammatory mediators. "Cancer" was the major significantly inhibited biological effect of GLSF treatment. These results demonstrate that GLSF can improve the therapeutic outcome for colorectal cancer through a mechanism involving suppression of NF-κB-regulated inflammation and carcinogenesis.
ABSTRACT
The ß-blocker carvedilol has been shown to prevent skin carcinogenesis in vitro and in vivo. Since systemic absorption of the ß-blocker may cause cardiovascular disturbance, we developed a carvedilol loaded transfersome for skin-targeted delivery. Transfersomes were prepared using phospholipids and surfactants at various ratios and characterized. One formulation (F18) selected for further analysis was composed of carvedilol, soy phosphatidylcholine, and Tween-80 at a ratio of 1:3:0.5, which had a particle size of 115.6 ± 8.7 nm, a zeta potential of 11.34 ± 0.67 mV, and an encapsulation efficiency of 93.7 ± 5.1%. F18 inhibited EGF-induced neoplastic transformation of mouse epidermal JB6 P+ cells at non-toxic concentrations, while only high concentrations induced cytotoxicity in JB6 P+ and human keratinocytes HaCaT. Compared to the free drug, F18 released through the dialysis membrane and permeated through the porcine ear skin at a slower rate, but similarly depositing the drug in the epidermis and dermis of the skin. Consistently, surface application of F18 on reconstructed full-thickness human skin showed slower drug permeation, while it suppressed ultraviolet-induced DNA damage, inflammatory gene expression, and apoptosis. These data indicate that transfersome is a promising topical delivery system of carvedilol for preventing ultraviolet-induced skin damage and carcinogenesis.
ABSTRACT
Analysis of the body mass index of pediatric patients with gastrointestinal complaints as a whole and by disease subgroup revealed a greater percentage of obese patients with constipation, gastroesophageal reflux, irritable bowel syndrome, encopresis, and functional abdominal pain compared with local and New Jersey control populations.
Subject(s)
Abdominal Pain/epidemiology , Constipation/epidemiology , Dyspepsia/epidemiology , Gastroesophageal Reflux/epidemiology , Irritable Bowel Syndrome/epidemiology , Obesity/epidemiology , Adolescent , Body Mass Index , Case-Control Studies , Child , Child, Preschool , Comorbidity , Female , Humans , Male , New Jersey/epidemiology , Young AdultABSTRACT
Wilforlide A (WA), an active compound in Tripterygium wilfordii Hook F (TW) which is a traditional Chinese medicine for treatment of autoimmune diseases, is a quality control marker for TW product. At present, the bioavailability/pharmacokinetics of WA is not known. Such information is not only essential to evaluate the relevance of WA as a quality control maker, but also important for future clinical efficacy studies. Therefore, a high-performance liquid chromatography-atmospheric pressure chemical ionization tandem mass spectrometric method (HPLC-APCI-MS/MS) was developed and applied to a bioavailability/pharmacokinetic study of WA. WA and celastrol (the internal standard, IS) were extracted by a liquid-liquid extraction method using methyl tert-butyl ether. Multiple reaction monitoring (MRM) scanning in positive ionization mode was used to monitor the transition of m/z 455.1 to 191.3 for WA and 451.3 to 201.2 for IS. This method was validated and applied to a pharmacokinetic study of WA in mice following intravenous administration (IV, 1.2â¯mg/kg), intraperitoneal injection (IP, 6â¯mg/kg) and oral administration (PO, 30â¯mg/kg). The lower limit of quantification (LLOQ) for WA was 10â¯ng/ml. The intra- and inter-day precision was found to be within 15.4% while the accuracy within 94.1-115.7% for all the quality control and LLOQ samples. The samples were stable under all the usual storage and experimental conditions. The terminal elimination half-lives were 14.7, 9.1 and 22.7â¯min following IV, IP and PO dosing, while the absolute bioavailability for IP and PO WA were 9.39% and 0.58% respectively. These results indicated that the HPLC-APCI-MS/MS assay was suitable for the pharmacokinetic study of WA. WA was found poorly absorbed when given orally and therefore it may not be a relevant marker for the oral TW products in the market.
Subject(s)
Chromatography, High Pressure Liquid/methods , Oleanolic Acid/analogs & derivatives , Tandem Mass Spectrometry/methods , Animals , Biological Availability , Linear Models , Male , Mice , Oleanolic Acid/blood , Oleanolic Acid/chemistry , Oleanolic Acid/pharmacokinetics , Reproducibility of Results , Sensitivity and SpecificityABSTRACT
Exploring traditional medicines may lead to the development of low-cost and non-toxic cancer preventive agents. Si-Wu-Tang (SWT), comprising the combination of four herbs, Rehmanniae, Angelica, Chuanxiong, and Paeoniae, is one of the most popular traditional Chinese medicines for women's diseases. In our previous studies, the antioxidant Nrf2 pathways were strongly induced by SWT in vitro and in vivo. Since Nrf2 activation has been associated with anticarcinogenic effects, the purpose of this study is to evaluate SWT's activity of cancer prevention. In the Ames test, SWT demonstrated an antimutagenic activity against mutagenicity induced by the chemical carcinogen 7,12-dimethylbenz(a)anthracene (DMBA). In JB6 P+ cells, a non-cancerous murine epidermal model for studying tumor promotion, SWT inhibited epidermal growth factor (EGF)-induced neoplastic transformation. The luciferase reporter gene assays demonstrated that SWT suppressed EGF-induced AP-1 and TNF-α-induced NF-κB activation, which are essential factors involved in skin carcinogenesis. In a DMBA-induced skin hyperplasia assay in 'Sensitivity to Carcinogenesis' (SENCAR) mice, both topical and oral SWT inhibited DMBA-induced epidermal hyperplasia, expression of the proliferation marker Proliferating cell nuclear antigen (PCNA), and H-ras mutations. These findings demonstrate, for the first time, that SWT prevents tumor promoter and chemical-induced carcinogenesis in vitro and in vivo, partly by inhibiting DNA damage and blocking the activation of AP-1 and NF-κB.
Subject(s)
Anticarcinogenic Agents/pharmacology , Cell Transformation, Neoplastic/drug effects , Drugs, Chinese Herbal/pharmacology , Hyperplasia/prevention & control , Skin/drug effects , 9,10-Dimethyl-1,2-benzanthracene/toxicity , Animals , Carrier Proteins/genetics , Carrier Proteins/metabolism , Cell Line, Tumor , DNA Damage/drug effects , Female , Gene Expression Regulation , Genes, Reporter , Hyperplasia/etiology , Mice , Mice, Inbred SENCAR , NF-E2-Related Factor 2/genetics , NF-E2-Related Factor 2/metabolism , NF-kappa B/genetics , NF-kappa B/metabolism , Skin/pathology , Transcription Factor AP-1/genetics , Transcription Factor AP-1/metabolism , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolismABSTRACT
In previous studies, the ß-blocker carvedilol inhibited EGF-induced epidermal cell transformation and chemical carcinogen-induced mouse skin hyperplasia. As exposure to ultraviolet (UV) radiation leads to skin cancer, the present study examined whether carvedilol can prevent UV-induced carcinogenesis. Carvedilol absorbs UV like a sunscreen; thus, to separate pharmacological from sunscreen effects, 4-hydroxycarbazole (4-OHC), which absorbs UV to the same degree as carvedilol, served as control. JB6 P+ cells, an established epidermal model for studying tumor promotion, were used for evaluating the effect of carvedilol on UV-induced neoplastic transformation. Both carvedilol and 4-OHC (1 µmol/L) blocked transformation induced by chronic UV (15 mJ/cm2) exposure for 8 weeks. However, EGF-mediated transformation was inhibited by only carvedilol but not by 4-OHC. Carvedilol (1 and 5 µmol/L), but not 4-OHC, attenuated UV-induced AP-1 and NF-κB luciferase reporter activity, suggesting a potential anti-inflammatory activity. In a single-dose UV (200 mJ/cm2)-induced skin inflammation mouse model, carvedilol (10 µmol/L), applied topically after UV exposure, reduced skin hyperplasia and the levels of cyclobutane pyrimidine dimers, IL1ß, IL6, and COX-2 in skin. In SKH-1 mice exposed to gradually increasing levels of UV (50-150 mJ/cm2) three times a week for 25 weeks, topical administration of carvedilol (10 µmol/L) after UV exposure increased tumor latency compared with control (week 18 vs. 15), decreased incidence and multiplicity of squamous cell carcinomas, while 4-OHC had no effect. These data suggest that carvedilol has a novel chemopreventive activity and topical carvedilol following UV exposure may be repurposed for preventing skin inflammation and cancer. Cancer Prev Res; 10(10); 598-606. ©2017 AACR.
Subject(s)
Anticarcinogenic Agents/pharmacology , Carbazoles/pharmacology , Carcinogenesis/drug effects , Neoplasms, Radiation-Induced/prevention & control , Propanolamines/pharmacology , Skin Neoplasms/prevention & control , Ultraviolet Rays/adverse effects , Administration, Cutaneous , Animals , Anticarcinogenic Agents/therapeutic use , Carbazoles/therapeutic use , Carcinogenesis/radiation effects , Carvedilol , Cell Transformation, Neoplastic/drug effects , Cell Transformation, Neoplastic/metabolism , Cell Transformation, Neoplastic/radiation effects , Disease Models, Animal , Epidermal Cells , Epidermal Growth Factor/metabolism , Epidermis/drug effects , Epidermis/pathology , Epidermis/radiation effects , Female , HEK293 Cells , Humans , Keratinocytes/drug effects , Keratinocytes/metabolism , Keratinocytes/radiation effects , Mice , Mice, Hairless , NF-kappa B/metabolism , Propanolamines/therapeutic use , Skin Neoplasms/etiology , Skin Neoplasms/pathology , Sunscreening Agents/pharmacology , Transcription Factor AP-1/metabolismABSTRACT
A leading cause of cancer chemotherapy failure is chemoresistance, which often involves multiple mechanisms. Chinese medicines (CM) usually contain multiple components which could potentially target many mechanisms simultaneously and may offer an advantage over single compounds that target one mechanism at a time. The purpose of this study was to investigate the chemosensitizing effect (CE) of a specific CM, Tripterygium wilfordii (TW), on prostate cancer cells resistant to docetaxel (Dtx) and identify the potential mechanisms. The CE of TW (in combination with Dtx) was evaluated in two Dtx resistant prostate cancer cell lines (PC3-TxR and DU145-TxR) and the efficacy of the combination for resistant PC3-TxR tumor was investigated using a xenograft mouse model. For mechanistic study, the inhibitory effect of TW on P-glycoprotein activity was assessed. In addition, novel gene targets of TW were identified using DNA microarray and quantitative PCR. Results showed that TW induced a CE of 8 and >38 folds in PC3-TxR and DU145-TxR cells, respectively with Dtx IC50 reversed back to that of the sensitive parent cells. An optimum dose of TW+Dtx significantly retarded tumor growth in mice compared to TW or Dtx alone. TW inhibited P-glycoprotein activity and induced a significant gene expression changes in genes related to angiogenesis, cell cycle regulation and differentiation. Our in vitro and in vivo studies demonstrate that TW in combination with Dtx was able to overcome the chemoresistance and suppress resistant prostate tumor growth via multi-mechanisms.
Subject(s)
Drug Resistance, Neoplasm , Drugs, Chinese Herbal/pharmacology , Plant Extracts/pharmacology , Prostatic Neoplasms/drug therapy , Tripterygium/chemistry , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Animals , Caco-2 Cells , Cell Cycle , Cell Line, Tumor , Cell Survival , Daunorubicin/chemistry , Docetaxel , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Humans , Inhibitory Concentration 50 , Male , Mice , Mice, SCID , Neoplasm Transplantation , Neovascularization, Pathologic , Prostatic Neoplasms/metabolism , Taxoids/pharmacologyABSTRACT
The stress-related catecholamine hormones and the α- and ß-adrenergic receptors (α- and ß-AR) may affect carcinogenesis. The ß-AR GRK/ß-arrestin biased agonist carvedilol can induce ß-AR-mediated transactivation of the EGFR. The initial purpose of this study was to determine whether carvedilol, through activation of EGFR, can promote cancer. Carvedilol failed to promote anchorage-independent growth of JB6 P(+) cells, a skin cell model used to study tumor promotion. However, at nontoxic concentrations, carvedilol dose dependently inhibited EGF-induced malignant transformation of JB6 P(+) cells, suggesting that carvedilol has chemopreventive activity against skin cancer. Such effect was not observed for the ß-AR agonist isoproterenol and the ß-AR antagonist atenolol. Gene expression, receptor binding, and functional studies indicate that JB6 P(+) cells only express ß2-ARs. Carvedilol, but not atenolol, inhibited EGF-mediated activator protein-1 (AP-1) activation. A topical 7,12-dimethylbenz(α)anthracene (DMBA)-induced skin hyperplasia model in SENCAR mice was utilized to determine the in vivo cancer preventative activity of carvedilol. Both topical and oral carvedilol treatment inhibited DMBA-induced epidermal hyperplasia (P < 0.05) and reduced H-ras mutations; topical treatment being the most potent. However, in models of established cancer, carvedilol had modest to no inhibitory effect on tumor growth of human lung cancer A549 cells in vitro and in vivo. In conclusion, these results suggest that the cardiovascular drug carvedilol may be repurposed for skin cancer chemoprevention, but may not be an effective treatment of established tumors. More broadly, this study suggests that ß-ARs may serve as a novel target for cancer prevention.
Subject(s)
Adrenergic beta-Antagonists/therapeutic use , Anticarcinogenic Agents/therapeutic use , Carbazoles/therapeutic use , Propanolamines/therapeutic use , Skin Neoplasms/prevention & control , 9,10-Dimethyl-1,2-benzanthracene/chemistry , Animals , Atenolol/therapeutic use , Carvedilol , Cell Adhesion , Cell Line , Cell Line, Tumor , Cell Proliferation , Drug Screening Assays, Antitumor , Female , Gene Expression Regulation, Neoplastic , HEK293 Cells , Humans , Isoproterenol/therapeutic use , Mice , Mutation , Neoplasm Transplantation , Transcription Factor AP-1/metabolismABSTRACT
Ginseng, a well-known herb, is often used in combination with anticancer drugs to enhance chemotherapy. Its wide usage as well as many documentations are often cited to support its clinical benefit of such combination therapy. However the literature based on objective evidence to make such recommendation is still lacking. The present review critically evaluated relevant studies reported in English and Chinese literature on such combination. Based on our review, we found good evidence from in vitro and in vivo animal studies showing enhanced antitumor effect when ginseng is used in combination with some anticancer drugs. However, there is insufficient clinical evidence of such benefit as very few clinical studies are available. Future research should focus on clinically relevant studies of such combination to validate the utility of ginseng in cancer.
ABSTRACT
INTRODUCTION: Nutraceutical is a food, or part of a food, used for the prevention and/or treatment of diseases. A number of nutraceuticals serve as candidates for development of prostate cancer chemopreventive agents because of promising epidemiological, preclinical and pilot clinical findings. Their mechanisms of action may involve an ability to target multiple molecular pathways in carcinogenesis without eliciting toxic side effects. AREAS COVERED: This review provides an overview of several nutraceuticals, including green tea polyphenol, omega-3 fatty acids, vitamin D, lycopene, genistein, quercetin, resveratrol and sulforaphane, for the clinical relevance to chemoprevention of prostate cancer. Their mechanisms of action on regulating key processes of carcinogenesis are also discussed. For each of these agents, a brief summary of completed or currently ongoing clinical trials related to the chemopreventive efficacy on prostate cancer is given. EXPERT OPINION: Even though a few clinical trials have been conducted, review of these results indicate that further studies are required to confirm the clinical efficacy and safety, and to provide a guidance on how to use nutraceuticals for optimal effect. Future cancer prevention clinical trials for the nutraceuticals should recruit men with an increased risk of prostate cancer.