RESUMEN
Cancer is the second deadliest disease worldwide. Although recent advances applying precision treatments with targeted (molecular and immune) agents are promising, the histological and molecular heterogeneity of cancer cells and huge mutational burdens (intrinsic or acquired after therapy) leading to drug resistance and treatment failure are posing continuous challenges. These recent advances do not negate the need for alternative approaches such as chemoprevention, the pharmacological approach to reverse, suppress or prevent the initial phases of carcinogenesis or the progression of premalignant cells to invasive disease by using non-toxic agents. Although data are limited, the success of several clinical trials in preventing cancer in high-risk populations suggests that chemoprevention is a rational, appealing and viable strategy to prevent carcinogenesis. Particularly among higher-risk groups, the use of safe, non-toxic agents is the utmost consideration because these individuals have not yet developed invasive disease. Natural dietary compounds present in fruits, vegetables and spices are especially attractive for chemoprevention and treatment because of their easy availability, high margin of safety, relatively low cost and widespread human consumption. Hundreds of such compounds have been widely investigated for chemoprevention and treatment in the last few decades. Previously, we reviewed the most widely studied natural compounds and their molecular mechanisms, which were highly exploited by the cancer research community. In the time since our initial review, many promising new compounds have been identified. In this review, we critically review these promising new natural compounds, their molecular targets and mechanisms of anticancer activity that may create novel opportunities for further design and conduct of preclinical and clinical studies.
Asunto(s)
Anticarcinógenos/farmacología , Antineoplásicos Fitogénicos/farmacología , Productos Biológicos/farmacología , Descubrimiento de Drogas , Extractos Vegetales/farmacología , Animales , Anticarcinógenos/toxicidad , Antineoplásicos Fitogénicos/toxicidad , Productos Biológicos/toxicidad , Humanos , Estructura Molecular , Extractos Vegetales/toxicidad , Relación Estructura-ActividadRESUMEN
Ethnopharmacological relevance Oral squamous cell carcinoma (OSCC) is one of the most common malignant tumors, seriously compromising patients' quality of life. Previous studies showed that Zengshengping (ZSP), a popular traditional Chinese medicine, has certain inhibiting effects on both oral precancerous lesions and OSCC. However, few reports underlined ZSP side effects such as liver toxicity, which limit its long-term application. Aim of the study was to evaluate the chemopreventive effect of a modified ZSPs formula on oral cancer in a hamster model. Its effect on hamster liver was also assessed. Materials and Methods The original medicine (ZSP-1) and other two formulas slightly different and called ZSP-2 and ZSP-3 were prepared ahead of time. DMBA (0.5%) was topically applied for 6 weeks to induce a premalignant lesion on hamsters' cheek pouch, then ZSP-1/2/3 were intragastrically administered for 8 weeks. Hamster treated with DMBA + each of the ZSPs represented the ZSP-1/2/3 groups, while those without ZSP-1/2/3 treatment represented the DMBA group. To assess the effect of ZSPs in the liver, intragastric administration of ZSP-1/2/3 was carried out to other groups of hamsters for 12 weeks and the blood was collected every two weeks to detect the hepatic function. Some of the hamsters were sacrificed at the end of 12 weeks, while the remaining animals were sacrificed after other 4 weeks to estimate the effect of ZSP-1/2/3 withdrawal on the liver. Results showed that tumor development in the ZSP-1/2/3 groups was less than that in DMBA group. BrdU, CD31 and COX-2 expression in the hyperplastic tissues was significantly lower in the ZSP-1/2/3 groups than that in the DMBA group. In addition, VEGF and COX-2 expression in ZSP-1/2/3 groups was lower while caspase-9 and p53 expression was higher than those in the DMBA group. Finally, PTEN expression in ZSP-1/2/3 groups was higher than that in the DMBA group. As regard the effect in the liver, ALP in the ZSP-1/2/3 groups was higher than that in the control group treated with an intragastric administration of ddH2O. After 4 weeks of withdrawal, the hamsters of the ZSP-3 group did not recover from the increase in ALP. Histopathology showed the presence of inflammatory lesions in each group after 12 weeks, especially in the ZSP-1/3 groups, and the number of apoptotic cells in the ZSP-3 group was higher than that in the other groups, without any recovery after withdrawal of the drug. At 12 weeks, the MDA in the ZSP-1 group was higher than that in the control group and the ZSP-2 group, but the difference disappeared after drug withdrawal because the MDA in the ZSP-1/3 groups decreased. Conclusions ZSP-2 possessed a chemopreventive effect against oral cancer by inhibiting inflammation, proliferation of tumor cells, generation of microvessels and by promoting tumor cell apoptosis. In addition, hepatotoxicity of ZSP-2, which might be related to oxidative stress injury, was reduced to some extent.
Asunto(s)
Anticarcinógenos/farmacología , Carcinogénesis/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Neoplasias de la Boca/prevención & control , Carcinoma de Células Escamosas de Cabeza y Cuello/prevención & control , 9,10-Dimetil-1,2-benzantraceno , Animales , Anticarcinógenos/toxicidad , Apoptosis/efectos de los fármacos , Carcinogénesis/inducido químicamente , Carcinogénesis/metabolismo , Carcinogénesis/patología , Proliferación Celular/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Composición de Medicamentos , Medicamentos Herbarios Chinos/toxicidad , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Masculino , Mesocricetus , Neoplasias de la Boca/inducido químicamente , Neoplasias de la Boca/metabolismo , Neoplasias de la Boca/patología , Neovascularización Patológica , Estrés Oxidativo/efectos de los fármacos , Transducción de Señal , Carcinoma de Células Escamosas de Cabeza y Cuello/inducido químicamente , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/patologíaRESUMEN
Cancer chemopreventive agents inhibit the formation of precursor lesions and/or the progression of these lesions to late stage disease. This approach to disease control has the potential to reduce the physical and financial costs of cancer in society. Several drugs that have been approved by the FDA for other diseases and have been extensively evaluated for their safety and pharmacokinetic/pharmacodynamic characteristics have the potential to be repurposed for use as cancer chemopreventive agents. These agents often mechanistically inhibit signaling molecules that play key roles in the carcinogenic process. The safety profile of agents is a primary concern when considering the administration of drugs for chemoprevention, as the drugs will be given chronically to high-risk, asymptomatic individuals. To decrease drug toxicity while retaining efficacy, several approaches are currently being explored. In this short review, we describe studies that use preclinical in vivo models to assess efficacy of alternative drug dosing strategies and routes of drug administration on chemopreventive drug efficacy. In vivo drug dosing strategies that reduce toxicity while retaining efficacy will pave the way for future cancer prevention clinical trials.
Asunto(s)
Anticarcinógenos/toxicidad , Evaluación Preclínica de Medicamentos/métodos , Neoplasias/prevención & control , Animales , Quimioprevención , Vías de Administración de Medicamentos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/prevención & control , HumanosRESUMEN
Copaiba oleoresins are used in alternative medicine as anti-inflammatory, antitumoral, and antimicrobial treatments. (-)-Copalic acid (CA) is the major diterpene found in exudates from Copaifera species. We have examined the genotoxicity and the chemopreventive potential of Copaifera multijuga oleoresin (CM) and CA. Genotoxicity assessment was examined with the peripheral blood micronucleus test and the comet assay (male Swiss mouse hepatocytes). In the chemoprevention study, we evaluated the effects of CM and CA on the formation of 1,2-dimethylhydrazine (DMH)-induced aberrant crypt foci (ACF) in male Wistar rat colon. Neither agent caused a significant increase in micronucleus frequency relative to controls, but the highest CM dose tested (400mg/kg b.w.) caused DNA damage in the comet assay. Both agents significantly reduced the frequency of DMH-induced ACF. Both CM and CA suppressed ACF formation and may have a protective effect against colon carcinogenesis.
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Anticarcinógenos/farmacología , Daño del ADN , Diterpenos/farmacología , Fabaceae/química , Micronúcleos con Defecto Cromosómico/inducido químicamente , Extractos Vegetales/farmacología , Focos de Criptas Aberrantes/prevención & control , Animales , Anticarcinógenos/aislamiento & purificación , Anticarcinógenos/toxicidad , Neoplasias del Colon/prevención & control , Ensayo Cometa , Diterpenos/aislamiento & purificación , Diterpenos/toxicidad , Relación Dosis-Respuesta a Droga , Hepatocitos/efectos de los fármacos , Hepatocitos/patología , Masculino , Ratones , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/toxicidad , Ratas WistarRESUMEN
CONTEXT: Hepatocellular carcinoma (HCC) is among the most well-known threatening tumours around the world, and the outlook remains bleak. Moringa oleifera Lam. (Moringaceae) exhibits antitumor, antioxidant and hepatoprotective properties. OBJECTIVES: To assess the chemo-prophylactic proficiency and other likely activities of Moringa oleifera leaf ethanol extract (MOLEE) against diethyl nitrosamine (DEN)-induced HCC. MATERIALS AND METHODS: Wistar rats were gastrogavaged with MOLEE (500 mg/kg) for one week and then gastrogavaged with MOLEE and DEN (10 mg/kg) for the following 16 weeks. The progressions of the histological components, serum biomarkers and oxidation of DNA of the liver tissues were resolved to assess the prophylactic impacts. The lipid oxidative biomarker, the cancer prevention agent status and apoptotic proteins were surveyed to assess the potential mechanisms. RESULTS: The MOLEE LD50 was estimated to be 5585 mg/kg. MOLEE (500 mg/kg) administration fundamentally repressed the expansion event of knobs and the normal knob number per knob-bearing livers prompted by DEN, enhanced hepatocellular appearance and altogether significantly decreased (p < 0.05) DEN-induced elevations in serum biochemical records and hepatic 8-hydroxy-2-deoxyguanosine (8-OHdG) levels by 29%. The robotic studies found that MOLEE disrupted the DEN-activated oxidative reactivity damage in rats by 46.8%. Curiously, the expression of Bcl-2, Bcl-xl and ß-arrestin-2 were fundamentally diminished (p < 0.05); however, the expression of Bax and caspase-3 were essentially (p < 0.05) upregulated. DISCUSSION AND CONCLUSIONS: The outcomes presume that MOLEE inspired critical defensive impacts against DEN-induced hepatocarcinogenesis that might be identified with the implementation of antioxidant activity and actuation of apoptosis.
Asunto(s)
Anticarcinógenos/farmacología , Antioxidantes/farmacología , Carcinoma Hepatocelular/prevención & control , Etanol/química , Neoplasias Hepáticas Experimentales/prevención & control , Moringa oleifera/química , Extractos Vegetales/farmacología , Hojas de la Planta/química , Solventes/química , Animales , Anticarcinógenos/aislamiento & purificación , Anticarcinógenos/toxicidad , Antioxidantes/aislamiento & purificación , Antioxidantes/toxicidad , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/metabolismo , Biomarcadores de Tumor/metabolismo , Carcinoma Hepatocelular/inducido químicamente , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Dietilnitrosamina , Dosificación Letal Mediana , Peroxidación de Lípido/efectos de los fármacos , Neoplasias Hepáticas Experimentales/inducido químicamente , Neoplasias Hepáticas Experimentales/metabolismo , Neoplasias Hepáticas Experimentales/patología , Masculino , Estrés Oxidativo/efectos de los fármacos , Fitoterapia , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/toxicidad , Plantas Medicinales , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Factores de TiempoRESUMEN
We recently reported that 4-methylthio-3-butenyl isothiocyanate (MTBITC) exerts chemopreventive effects on the rat esophageal carcinogenesis model at a low dose of 80 ppm in a diet. In contrast, some isothiocyanates (ITCs) have been reported to cause toxic effects, promotion activity, and/or carcinogenic potential in the urinary bladder of rats. In the present study, we investigated whether MTBITC had toxic effects in the urinary bladder similar to other ITCs, such as phenethyl ITC (PEITC). First, to examine the early toxicity of MTBITC, rats were fed a diet supplemented with 100, 300 or 1000 ppm MTBITC for 14 days. Treatment with 1000 ppm MTBITC caused increased organ weights and histopathological changes in the urinary bladder, producing lesions similar to those of 1000 ppm PEITC. In contrast, rats treated with 100 or 300 ppm MTBITC showed no signs of toxicity. Additionally, we performed in vivo genotoxicity studies to clarify whether MTBITC may exhibit a carcinogenic potential through a genotoxic mechanism in rats. Rats were treated with MTBITC for 3 days at doses of 10, 30 or 90 mg kg-1 body weight by gavage, and comet assays in the urinary bladder and micronucleus assays in the bone marrow were performed. No genotoxic changes were observed after treatment with MTBITC at all doses. Overall, these results suggested that the effects of MTBITC in the rat urinary bladder are less than those of PEITC, but that MTBITC could have toxic effects through a nongenotoxic mechanism in the urinary bladder of rats at high doses. Copyright © 2016 John Wiley & Sons, Ltd.
Asunto(s)
Anticarcinógenos/toxicidad , Isotiocianatos/toxicidad , Mutágenos/toxicidad , Enfermedades de la Vejiga Urinaria/inducido químicamente , Animales , Células de la Médula Ósea/efectos de los fármacos , Daño del ADN , Ingestión de Alimentos/efectos de los fármacos , Masculino , Pruebas de Mutagenicidad , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Endogámicas F344 , Vejiga Urinaria/efectos de los fármacos , Vejiga Urinaria/patología , Enfermedades de la Vejiga Urinaria/genética , Enfermedades de la Vejiga Urinaria/patologíaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Crateva adansonii DC is a plant traditionally used in Cameroon to treat constipation, asthma, snakebites, postmenopausal complaints and cancers. AIM: The anticancer potential of the dichloromethane/methanol extract of C. adansonii stem barks was investigated using human breast cancer cell and 7,12 dimethylbenz(a)anththracene (DMBA)-induced mammary tumorigenesis model in rats. MATERIAL AND METHODS: The cytotoxicity of C. adansonii extract was assessed in vitro towards breast carcinoma (MCF-7 and MDA-MB-231) and non-tumoral cell lines (NIH/3T3 and HUVEC) by Alamar Blue assay. Furthermore, in vivo studies were performed on female Wistar rats treated either with C. adansonii extract at a dose of 75 or 300mg/kg body weight or with tamoxifen (3.3mg/kg body weight), starting 1 week prior DMBA treatment and lasted 12 weeks. The investigation focused on tumour burden, tumour DNA fingerprint, morphological, histological, hematological, and biochemical parameters. RESULTS: CC50 values for the in vitro assays were 289µg/mL against MCF-7 cells and >500µg/mL in others cells, leading to a selectivity index ≥1.73. C. adansonii extract significantly (p<0.001) revealed in vivo the reduction of the cumulative tumour yield (87.23%), total tumour burden (88.64%), average tumour weight (71.11%) and tumour volume (78.07%) at the dose of 75mg/kg as compared to DMBA control group. A weak effect was also observed at 300mg/kg. This extract showed a moderate hyperplasia at the dose of 75mg/kg while at 300mg/kg no significant change was noted as compared to DMBA group. It protected rats from the DNA alteration induced by DMBA and increased antioxydant enzymes activities in mammary gland tissue homogenates. In addition, Ultra-High Performance Liquid Chromatography/ESI-QTOF-Mass Spectrometry analysis of C. adansonii extract detected structure-related of many well-known anticancer agents such as flavane gallate, flavonol, phenylpropanoïds, sesquiterpene derivatives, gallotannins and lignans. The LD50 of C. adansonii was estimated to be greater than 5000mg/kg. CONCLUSIONS: These aforementioned results suggest that the C. adansonii extract may possess antitumor constituents, which could combat breast cancer and prevent chemically-induced breast cancer in rats.
Asunto(s)
Anticarcinógenos/farmacología , Antineoplásicos Fitogénicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Capparaceae/química , Neoplasias Mamarias Experimentales/prevención & control , Extractos Vegetales/farmacología , 9,10-Dimetil-1,2-benzantraceno , África , Animales , Anticarcinógenos/química , Anticarcinógenos/aislamiento & purificación , Anticarcinógenos/toxicidad , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/toxicidad , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Cromatografía Liquida , Daño del ADN/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Etnobotánica , Femenino , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/patología , Humanos , Concentración 50 Inhibidora , Dosificación Letal Mediana , Células MCF-7 , Neoplasias Mamarias Experimentales/inducido químicamente , Neoplasias Mamarias Experimentales/patología , Medicinas Tradicionales Africanas , Ratones , Estructura Molecular , Células 3T3 NIH , Estrés Oxidativo/efectos de los fármacos , Fitoterapia , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/toxicidad , Plantas Medicinales , Ratas Wistar , Espectrometría de Masa por Ionización de Electrospray , Tamoxifeno/farmacología , Factores de Tiempo , Carga Tumoral/efectos de los fármacosRESUMEN
Proanthocyanidins are among the most abundant constituents in pine bark extracts (PBEs). This review summarizes medical research on PBEs from Pinus pinaster, Pinus radiata, Pinus massoniana, and other less well characterized species. The precise mechanisms of the important physiologic functions of PBE components remain to be elucidated, but there is evidently great potential for the identification and development of novel antioxidant, anti-inflammatory, cardiovascular, neuroprotective, and anticancer medicines. Although toxicological data for PBEs are limited, no serious adverse effects have been reported. PBEs, therefore, may have potential as nutraceuticals and pharmaceuticals and should be safe for use as food ingredients.
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Pinus/química , Corteza de la Planta/química , Extractos Vegetales/farmacología , Animales , Antiinflamatorios/farmacocinética , Antiinflamatorios/farmacología , Antiinflamatorios/toxicidad , Anticarcinógenos/farmacocinética , Anticarcinógenos/farmacología , Anticarcinógenos/toxicidad , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Antineoplásicos/toxicidad , Antioxidantes/farmacocinética , Antioxidantes/farmacología , Antioxidantes/toxicidad , Cardiotónicos/farmacocinética , Cardiotónicos/farmacología , Cardiotónicos/toxicidad , Humanos , Factores Inmunológicos/farmacocinética , Factores Inmunológicos/farmacología , Factores Inmunológicos/toxicidad , Metabolismo de los Lípidos/efectos de los fármacos , Fármacos Neuroprotectores/farmacocinética , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/toxicidad , Extractos Vegetales/farmacocinética , Extractos Vegetales/toxicidad , Proantocianidinas/farmacocinética , Proantocianidinas/farmacología , Proantocianidinas/toxicidadRESUMEN
The aqueous extract of Peltophorum pterocarpum (Fabaceae) wood exhibited potent inhibitory effects against EpsteinBarr virus early antigen (EBV-EA) activation induced with 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells and against melanogenesis in α-melanocyte-stimulating hormone (α-MSH)-stimulated B16 melanoma cells, as well as potent 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical-scavenging activity. Two phenolic acid derivatives, bergenin (1) and gallic acid (2), were isolated from the ethyl acetate (AcOEt)-soluble fraction obtained from the extract. Compound 1 exhibited potent inhibitory effect against EBV-EA activation and against skin tumor promotion in an in vivo two-stage mouse skin carcinogenesis test based on 7,12-dimethylbenz[a]anthracene (DMBA) as initiator, and with TPA as promoter. Both compounds 1 and 2 exhibited melanogenesis-inhibitory activities in α-MSH-stimulated B16 melanoma cells, and, in addition, compound 2 showed strong DPPH radical-scavenging activity.
Asunto(s)
Anticarcinógenos/química , Benzopiranos/química , Fabaceae/química , Depuradores de Radicales Libres/química , Ácido Gálico/química , Animales , Anticarcinógenos/farmacología , Anticarcinógenos/uso terapéutico , Anticarcinógenos/toxicidad , Antígenos Virales/química , Antígenos Virales/metabolismo , Apoptosis/efectos de los fármacos , Benzopiranos/farmacología , Benzopiranos/uso terapéutico , Línea Celular Tumoral , Fabaceae/metabolismo , Depuradores de Radicales Libres/aislamiento & purificación , Ácido Gálico/farmacología , Ácido Gálico/uso terapéutico , Células HL-60 , Humanos , Melaninas/antagonistas & inhibidores , Melaninas/metabolismo , Ratones , Extractos Vegetales/química , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/prevención & controlRESUMEN
SHetA2 is a heteroarotinoid that has shown selective inhibition of cancer cell growth and an induction of apoptosis without activation of nuclear retinoic acid receptors. In the rat study, SHetA2 was administered in 1% aqueous methylcellulose/0.2% Tween 80 by oral gavage at 0, 100, 500, and 2,000 mg/kg/day for 28 days. The high-dose administration induced decreased activity in male rats, decreased body-weight gains and food consumption, and changes in organ weights. The major metabolite of SHetA2 in rat plasma was monohydroxy SHetA2, which was considerably higher than the parent compound after oral and intravenous administration. Pharmacokinetic analysis showed extremely low (<1%) systemic bioavailability of SHetA2 for all doses tested. The dose of 2,000 mg/kg/day was considered as the lowest observed adverse effect level. The no observed adverse effect level (NOAEL) was 500 mg/kg/day. In the dog study, no toxicity of SHetA2 in 30% aqueous Solutol(®) HS 15 was observed in any tested dose groups (0, 100, 400, and 1,500 mg/kg/day). The major metabolite of SHetA2 in dog plasma was also monohydroxy SHetA2, which was equal to or lower than the parent compound after oral administration. SHetA2 levels in dog plasma were notably higher, when compared to levels in rat plasma. However, exposure was not dose proportional, as exemplified by a lack of proportional increase in maximum concentration or area under the plasma concentration-time curve with increasing dose. The NOAEL was not established and was considered to be above 1,500 mg/kg/day.
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Anticarcinógenos/farmacocinética , Anticarcinógenos/toxicidad , Cromanos/farmacocinética , Cromanos/toxicidad , Tionas/farmacocinética , Tionas/toxicidad , Administración Oral , Glándulas Suprarrenales/efectos de los fármacos , Glándulas Suprarrenales/patología , Animales , Anticarcinógenos/administración & dosificación , Área Bajo la Curva , Cromanos/administración & dosificación , Perros , Ingestión de Alimentos/efectos de los fármacos , Femenino , Masculino , Actividad Motora/efectos de los fármacos , Nivel sin Efectos Adversos Observados , Tamaño de los Órganos/efectos de los fármacos , Próstata/efectos de los fármacos , Próstata/patología , Ratas , Ratas Sprague-Dawley , Especificidad de la Especie , Tionas/administración & dosificación , Pruebas de Toxicidad , Aumento de Peso/efectos de los fármacosRESUMEN
Anticancer drugs are classified as vesicant, irritant, and nonvesicant drugs on the basis of frequency of their vascular disorder. In this study, we compared the injuring effects of three typical anticancer drugs of each class on porcine aorta endothelial cells (PAECs). The concentration inducing 50% cell viability inhibition was lower in the order of vesicant, irritant, and nonvesicant drugs. These results suggest that injuring effects of anticancer drugs on PAECs may be relevant as an indicator of frequency of their vascular disorder, and that this experimental model may be useful for the study of vascular disorder.
Asunto(s)
Anticarcinógenos/toxicidad , Evaluación Preclínica de Medicamentos/métodos , Células Endoteliales/efectos de los fármacos , Irritantes/toxicidad , Animales , Aorta/citología , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , PorcinosRESUMEN
The advance in the area of synthesis and reactivity of organoselenium, as well as the discovery that selenium was the cause of severe intoxication episodes of livestock in the 1930s and the subsequent determination that selenium was an essential trace element in the diet for mammals, has motivated intense studies of the biological properties of both organic and inorganic selenium compounds. In this review, we shall cover a wide range of toxicological and pharmacological effects, in which organoselenium compounds are involved but the effects of inorganic compounds were not discussed in detail here. The molecular toxicity of inorganic selenium was described in relation to its interaction with endogenous -SH groups to allow a comparison with that of synthetic organoselenium compounds. Furthermore, in view of the recent points of epidemiological evidence that overexposure to selenium can facilitate the appearance of chronic degenerative diseases, we also briefly revised the history of selenium toxicity and physiology and how environmental selenium can reach inside the mammalian cells. The biological narrative of the element selenium, in the last century, has been marked by a contrast between its toxic and its beneficial effects. Thus, the potential therapeutic use of simple organoselenium compounds has not yet been sufficiently explored and, consequently, we cannot discard this class of compounds as promising pharmaceutical agents. In effect, the future of the organochalcogens as pharmacological agents will depend on more detailed toxicological studies in the oncoming years.
Asunto(s)
Antiinflamatorios no Esteroideos/toxicidad , Anticarcinógenos/toxicidad , Azoles/toxicidad , Compuestos de Organoselenio/toxicidad , Selenio/toxicidad , Animales , Antiinflamatorios no Esteroideos/farmacología , Anticarcinógenos/farmacología , Azoles/química , Azoles/farmacología , Humanos , Isoindoles , Compuestos de Organoselenio/química , Compuestos de Organoselenio/farmacología , Estrés Oxidativo , Selenio/química , Selenio/farmacología , Compuestos de Sulfhidrilo/metabolismoRESUMEN
Previous studies have shown that activities of tyrosine kinases and secretion of the active form of matrix metalloproteinase-2 (MMP-2) are correlated with promotion of tumor growth, while apoptotic cell death in cancer cells is correlated with anti-cancer effects. Although arsenic has been reported to have both cancer-promoting and anti-cancer effects, the mechanisms of the arsenic-mediated bidirectional effects remain unknown. We examined the effects of arsenic on both proto-oncogene c-RET-transfected NIH3T3 cells with benign characters and oncogenic RET-MEN2A-transfected NIH3T3 cells with malignant characters. Arsenic promoted not only c-RET tyrosine kinase activity but also genetically activated RET-MEN2A kinase activity with promotion of dimer formation of RET proteins. Arsenic also increased secretion of the active form of MMP-2 in both RET-MEN2A-transfectants and c-RET-transfectants. On the other hand, arsenic promoted poly-(ADP-ribose) polymerase (PARP) degradation and cell death in both malignant and non-malignant cells. Interestingly, l-cysteine inhibited the arsenic-mediated tumor-promoting effects (activation of kinases and MMP-2 secretion) but not arsenic-mediated anti-cancer effects (PARP degradation and cell death). Our results suggest redox-linked regulation of arsenic-mediated activities of kinases and MMP-2 secretion but not arsenic-mediated cell death. Our results also suggest that l-cysteine is an ideal supplement that inhibits arsenic-mediated tumor-promoting effects without affecting arsenic-mediated anti-cancer effects.
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Anticarcinógenos/toxicidad , Arsenitos/toxicidad , Carcinógenos Ambientales/toxicidad , Cisteína/farmacología , Inhibidores Enzimáticos/toxicidad , Células 3T3 NIH/efectos de los fármacos , Compuestos de Sodio/toxicidad , Animales , Supervivencia Celular/efectos de los fármacos , Interacciones Farmacológicas , Metaloproteinasa 2 de la Matriz/metabolismo , Ratones , Neoplasia Endocrina Múltiple Tipo 2a/genética , Células 3T3 NIH/metabolismo , Células 3T3 NIH/patología , Poli(ADP-Ribosa) Polimerasas/metabolismo , TransfecciónRESUMEN
The essential oil from the bark of Cinnamomum zeylanicum Blume was analyzed by GC-MS and bioassays were carried out. Nine constituents representing 99.24% of the oil were identified by GC-MS. The major compounds in the oil were (E)-cinnamaldehyde (68.95%), benzaldehyde (9.94%) and (E)-cinnamyl acetate (7.44%). The antimicrobial activity of the oil was investigated in order to evaluate its efficacy against 21 bacteria and 4 Candida species, using disc diffusion and minimum inhibitory concentration methods. The essential oil showed strong antimicrobial activity against all microorganisms tested. The cytotoxic and apoptotic effects of the essential oil on ras active (5RP7) and normal (F2408) fibroblasts were examined by MTT assay and acridine orange/ethidium bromide staining, respectively. The cytotoxicity of the oil was quite strong with IC(50) values less than 20 µg/mL for both cell lines. 5RP7 cells were affected stronger than normal cells. Morphological observation of apoptotic cells indicated the induction of apoptosis at the high level of the oil, especially in 5RP7 cells. The present study showed the potential antimicrobial and anticarcinogenic properties of the essential oil of cinnamon bark, indicating the possibilities of its potential use in the formula of natural remedies for the topical treatment of infections and neoplasms.
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Antibacterianos , Cinnamomum zeylanicum/química , Aceites Volátiles , Aceites de Plantas , Acroleína/análogos & derivados , Acroleína/análisis , Animales , Antibacterianos/química , Antibacterianos/toxicidad , Anticarcinógenos/química , Anticarcinógenos/toxicidad , Apoptosis/efectos de los fármacos , Benzaldehídos/análisis , Línea Celular , Supervivencia Celular/efectos de los fármacos , Cinamatos/análisis , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Cromatografía de Gases y Espectrometría de Masas , Pruebas de Sensibilidad Microbiana , Aceites Volátiles/química , Aceites Volátiles/toxicidad , Corteza de la Planta/química , Aceites de Plantas/química , Aceites de Plantas/toxicidad , Ratas , Sales de Tetrazolio/metabolismo , Tiazoles/metabolismoRESUMEN
PURPOSE: The purpose of this study was to evaluate the preclinical safety of intravitreal genistein in rabbit eyes over a short-term period. METHODS: Twelve New Zealand albino rabbits were selected for this study. Four concentrations of genistein (LC Laboratories, Woburn, MA) were prepared: 24 mg/0.1 mL, 135 mg/0.1 mL, 270 mg/0.1 mL, and 540 mg/0.1 mL. Each concentration was injected intravitreally in one eye of three rabbits. As a control, the vehicle solution was injected into the other eye of each animal. Retinal safety of intravitreal genistein was studied with electroretinography and histologic examination in rabbits. Electroretinography recordings were made before the injection and 3 weeks after the injection. Eventually, the rabbits were killed and the retinas were examined by light microscopy. Immunohistochemical staining with caspase-3 and caspase-9 was also performed to evaluate apoptotic expression in all study and control eyes. RESULTS: Electroretinography studies showed no significant difference between control and genistein-injected eyes at any of the doses in the rabbit model. Histologic examination showed no retinal abnormality in the rabbits injected with different concentrations of genistein. Immunohistochemical staining with caspase-3 and caspase-9 showed no different apoptotic protein expression in any study or control eyes. CONCLUSION: Our results indicate that genistein is a safe intravitreal drug in the rabbit model up to 540 mg. If proven safe and efficacious in human studies, intravitreal injection of genistein could be considered a treatment alternative for ocular neovascularisation in selected cases.
Asunto(s)
Anticarcinógenos/toxicidad , Electrorretinografía/efectos de los fármacos , Genisteína/toxicidad , Fitoestrógenos/toxicidad , Retina/efectos de los fármacos , Animales , Caspasa 3/metabolismo , Caspasa 9/metabolismo , Evaluación Preclínica de Medicamentos , Inyecciones Intravítreas , Modelos Animales , Conejos , Retina/enzimología , Retina/patologíaRESUMEN
Our ability to detect and treat most primary cancers has improved dramatically given the advances in our understanding of cancer biology. However, with increased life expectancy and our inability to treat or cure advanced stages of cancers, the number of cancer-related deaths is expected to double in the next decade. Epidemiological studies suggest that dietary factors are an important aspect that influences cancer risk. Despite a lack of scientific evidence in most cases, cancer patients have whole-heartedly accepted the concept of "alternative medicine" using natural compounds and spent more than $1B a year on herbal supplements. Given the significant toxicity-associated problems with current long-term standard of care, scientifically validated natural supplements can serve as novel and effective alternative strategies for effective cancer management. We will discuss the utility of natural products in modulating critical signaling pathways for effective cancer prevention with special emphasis on prostate cancer and their potential translational benefit.
Asunto(s)
Anticarcinógenos/uso terapéutico , Productos Biológicos/uso terapéutico , Phellodendron/química , Neoplasias de la Próstata/prevención & control , Anticarcinógenos/aislamiento & purificación , Anticarcinógenos/toxicidad , Productos Biológicos/aislamiento & purificación , Productos Biológicos/toxicidad , Humanos , Masculino , Corteza de la Planta/química , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/uso terapéutico , Extractos Vegetales/toxicidad , Neoplasias de la Próstata/tratamiento farmacológicoRESUMEN
Evodiamine (1), a biologically active alkaloid isolated from Evodia rutaecarpa (known in Chinese as Wu-Chu-Yu), has antioxidant, anti-inflammatory, and anticancer activities. It has recently been demonstrated that the cytotoxic activities of 1 might be due to its ability to inhibit cell growth and induce apoptosis. In this study, we investigated the effects of 1 on growth and apoptosis in COLO-205 cells by MTT assay, fluorescence microscopy, transmission electron microscopy, DNA fragmentation assay, flow cytometry, immunohistochemical analysis, Western blotting, and caspase-3 activity assay. Our data revealed that 1 could significantly inhibit COLO-205 cell proliferation in a dose-dependent manner, and 1-treated COLO-205 cells displayed typical morphological apoptotic characteristics and formation of DNA ladders in agarose gel electrophoresis. The COLO-205 cell cycle was arrested in G(2)/M phase by 1. Meanwhile, 1 increased the expression of Bax and p53, decreased the expression of Bcl-2, lowered the mitochondrial transmembrane potential, and induced the activation of caspase-3. These activities may contribute to the anticarcinogenic action of 1.
Asunto(s)
Anticarcinógenos/toxicidad , Apoptosis , Carcinoma/metabolismo , Neoplasias Colorrectales/metabolismo , Extractos Vegetales/toxicidad , Quinazolinas/toxicidad , Anticarcinógenos/química , Anticarcinógenos/aislamiento & purificación , Carcinoma/patología , Caspasa 3/metabolismo , Ciclo Celular , Proliferación Celular , Neoplasias Colorrectales/patología , Evodia/química , Fase G2 , Humanos , Potenciales de la Membrana , Mitocondrias/efectos de los fármacos , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Quinazolinas/química , Quinazolinas/aislamiento & purificación , Células Tumorales Cultivadas , Proteína p53 Supresora de Tumor/metabolismo , Proteína X Asociada a bcl-2/metabolismoRESUMEN
HESA-A is a natural compound of herbal-marine origin with cytotoxic and antitumor effects. The anticancer effects of HESA-A has been the subject of both in vivo and in vitro studies. This study was to investigate the mechanism of HESA-A teratogenicity. We assessed the HESA-A-induced apoptosis in mouse fetus in vitro by using the vital staining and TUNNEL methods. HESA-A, in lower doses, had no significant effect on apoptosis but, in higher doses of 20 and 40 muL, increased cell death. A dose of 100 muL induced the cell death with both apoptosis and necrosis mechanisms. HESA-A changed the cell-death pattern; in moderate doses of the drug, the apoptosis-to-necrosis ratio was more than 1, and in higher doses, this ratio was less than 1.
Asunto(s)
Anticarcinógenos/toxicidad , Apoptosis/fisiología , Embrión de Mamíferos/efectos de los fármacos , Preparaciones de Plantas/toxicidad , Teratógenos/toxicidad , Animales , Anticarcinógenos/química , Apoptosis/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Técnicas de Cultivo de Embriones , Embrión de Mamíferos/patología , Femenino , Etiquetado Corte-Fin in Situ , Indicadores y Reactivos/química , Masculino , Metales Pesados/análisis , Ratones , Ratones Endogámicos BALB C , Necrosis/inducido químicamente , Rojo Neutro/química , Preparaciones de Plantas/química , EmbarazoRESUMEN
In view of safety concerns surrounding the use of pharmaceuticals such as nonsteroidal anti-inflammatory drugs and tamoxifen as cancer chemopreventive agents, potentially innocuous phytochemicals derived from the diet are considered attractive alternatives. However, results from cancer chemoprevention trials of dietary agents have been disappointing to date, as promising activities observed in rodent models and cells in vitro have not translated into clinical success. This may be partly due to the development process for these agents, which is complex for a number of reasons; the definitive end point, inhibition of carcinogenesis, requires large numbers of individuals followed-up over many years. Furthermore, whereas biomarkers are frequently used as surrogate efficacy end points to expedite the process, biomarker assessment and validation has proven difficult because dietary agents exert multiple actions with an unknown hierarchy of biological importance. These factors have made determining the dose for clinical investigation extremely challenging, and at present, there are no defined strategies for rationally identifying the most appropriate doses. In this commentary, the complexities involved in the development of dietary chemoprevention agents are discussed, and a tentative route towards selection of the optimal clinical dose is proposed. The approach highlights the need to conduct long-term preclinical studies with realistic concentrations that are achievable in human tissues and the importance of efficacy biomarkers that are intrinsically linked to the key mechanisms of action. A more logical design of studies should increase the likelihood that the encouraging preclinical results observed for many phytochemicals translate into tangible clinical benefit.