RESUMO
Plants of the Calea genus have been reported to contain lipophilic compounds, such as sesquiterpene lactones, with cytotoxic effect against different cancer cell lines. The aim of this manuscript was to investigate the chemical profile and cytotoxic activity of different fractions from Calea phylolepis leaves on different human cancer cell lines. The fractions were prepared using solvent extraction of increasing polarity, yielding hexane, ethyl acetate and methanolic fractions. All fractions were chemically analysed by thin layer chromatography (TLC), and their cytotoxic activity against HT-29 (colon adenocarcinoma), MCF-7 (breast cancer), U-251MG (malignant glioblastoma) and L929 (mouse fibroblast) cell lines was investigated. Among these, the hexane and ethyl acetate fractions showed higher cytotoxic effects, while the methanolic fraction did not show any cytotoxic effects. The major bioactive compound from the hexane fraction (12.15%) was isolated using chromatographic methods and was identified by nuclear magnetic resonance spectroscopy (NMR) and gas chromatography-mass spectrometry (GC-MS) analysis as 6-epi-ß-verbesinol coumarate. This compound showed activity against breast cancer cells (IC50 = 5.8 ± 1.0 µg/ml), similar to etoposide. Furthermore, 6-epi-ß-verbesinol coumarate showed low cytotoxicity to normal fibroblast cells, suggesting a high selectivity index (SI = 7.39) against breast cancer cells.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Asteraceae/química , Neoplasias da Mama/tratamento farmacológico , Extratos Vegetais/farmacologia , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/toxicidade , Linhagem Celular , Linhagem Celular Tumoral , Feminino , Fibroblastos/efeitos dos fármacos , Cromatografia Gasosa-Espectrometria de Massas , Células HT29 , Humanos , Concentração Inibidora 50 , Células MCF-7 , Espectroscopia de Ressonância Magnética , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Extratos Vegetais/administração & dosagem , Extratos Vegetais/toxicidade , Folhas de PlantaRESUMO
Natural products have played a pivotal role for the discovery of anticancer drugs. Tonantzitlolones are flexibilan-type diterpenes rare in nature; therefore, few reports have shown antiviral and cytotoxic activities. This study aimed to investigate the in vivo antitumor action of Tonantzitlolone B (TNZ-B) and its toxicity. Toxicity was evaluated in mice (acute and micronucleus assays). Antitumor activity of TNZ-B (1.5 or 3 mg/kg intraperitoneally - i.p.) was assessed in Ehrlich ascites carcinoma model. Angiogenesis and reactive oxygen species (ROS) and nitric oxide (NO) production were also investigated, in addition to toxicological effects after 7-day treatment. The LD50 (lethal dose 50%) was estimated at around 25 mg/kg (i.p.), and no genotoxicity was recorded. TNZ-B reduced the Ehrlich tumor's volume and total viable cancer cell count (p < 0.001 for both). Additionally, TNZ-B reduced peritumoral microvessel density (p < 0.01), suggesting antiangiogenic action. Moreover, a decrease was observed on ROS (p < 0.05) and nitric oxide (p < 0.001) levels. No significant clinical findings were observed in the analysis of biochemical, hematological, and histological (liver and kidney) parameters. In conclusion, TNZ-B exerts antitumor and antiangiogenic effects by reducing ROS and NO levels and has weak in vivo dose-repeated toxicity. These data contribute to elucidate the antitumor action of TNZ-B and point the way for further studies with this natural compound as an anticancer drug.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Carcinoma de Ehrlich/tratamento farmacológico , Diterpenos/farmacologia , Euphorbiaceae/química , Compostos Macrocíclicos/farmacologia , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/toxicidade , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/toxicidade , Linhagem Celular Tumoral , Diterpenos/administração & dosagem , Diterpenos/toxicidade , Relação Dose-Resposta a Droga , Feminino , Dose Letal Mediana , Compostos Macrocíclicos/administração & dosagem , Compostos Macrocíclicos/toxicidade , Camundongos , Testes para Micronúcleos , Óxido Nítrico/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
BACKGROUND: Drugs used for the treatment of diseases associated with chronic inflammation, such as cancer and rheumatoid arthritis have the potential to cause undesirable side-effects, which might result in patients ending treatment prematurely. However, plants are a viable option for the treatment of inflammatory diseases. In this study, we assessed the in vivo and in vitro anti-inflammatory activity, and the antitumor effects of the chloroform extract of Salvia ballotiflora (ECL). The pro-apoptotic effects of ECL in CT26 cells were also determined. METHODS: The chloroform extract of Salvia ballotiflora (ECL) was standardized using 19-deoxyicetexone (DEOX) as a phytochemical marker. The anti-inflammatory activity of ECL was determined on acute and chronic inflammatory models using the TPA-induced mouse ear edema assay. The antitumor activity of ECL was evaluated by the subcutaneous inoculation of CT26 cells on the back of Balb/c mice. In vitro CT26 cell death induced by ECL was determined by Annexin V/propidium iodide staining assay using flow cytometry. ECL and the diterpenes isolated from the chloroform extract included 19-deoxyicetexone (DEOX), icetexone (ICT), and 7,20-dihydroanastomosine (DAM), which were tested in LPS-stimulated J774A.1 macrophages to quantify pro-inflammatory cytokine levels. The in vitro anti-arthritic activity of ECL was determined using the bovine serum protein (BSP) denaturation assay. RESULTS: ECL exerted anti-inflammatory activities in acute (84% of inhibition, 2 mg/ear) and chronic models (62.71%, at 100 mg/kg). ECL showed antitumor activity at 200 mg/kg and 300 mg/kg, reducing tumor volume by 30 and 40%, respectively. ECL (9.5 µg/mL) induced in vitro apoptosis in CT26 cells by 29.1% (48 h of treatment) and 93.9% (72 h of treatment). ECL (10 µg/ml) decreased levels of NO (53.7%), pro-inflammatory cytokines IL-6 (44.9%), IL-1ß (71.9%), and TNF-α (40.1%), but increased the production of the anti-inflammatory cytokine IL-10 (44%). The diterpenes DEOX, ICT, and DAM decreased levels of NO (38.34, 47.63, 67.15%), IL-6 (57.84, 60.45, 44.26%), and TNF-α (38.90, 31.30, 32.83%), respectively. ECL showed in vitro antiarthritic activity (IC50 = 482.65 µg/mL). CONCLUSIONS: ECL exhibited anti-inflammatory and anti-tumor activities. Furthermore, the diterpenes DEOX, DAM, and ICT showed anti-inflammatory activity by reducing levels of NO, TNF-α, and IL-6.
Assuntos
Anti-Inflamatórios não Esteroides/isolamento & purificação , Antineoplásicos Fitogênicos/isolamento & purificação , Diterpenos/farmacologia , Extratos Vegetais/farmacologia , Salvia/química , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/toxicidade , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/toxicidade , Apoptose/efeitos dos fármacos , Artrite/tratamento farmacológico , Linhagem Celular Tumoral , Clorofórmio , Citocinas/imunologia , Diterpenos/isolamento & purificação , Diterpenos/toxicidade , Edema/tratamento farmacológico , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico/metabolismo , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/toxicidade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The ionic gelation method was used to study the effect of the crosslinking agent, sodium tripolyphosphate on average particle size (Dp) and zeta potential (ζp) of chitosan microparticles (CSMP) unloaded and loaded with trans-cinnamaldehyde (TCIN). The obtained values of Dp and ζp trend as 117.6⯱â¯0.4â¯≤â¯Dpâ¯≤â¯478.5⯱â¯3.5â¯nm and +27.8⯱â¯1.3â¯≤â¯Î¶pâ¯≤â¯+103.5⯱â¯4.2â¯mV, respectively. The entrapment efficiency of TCIN in CSMP was 9.1⯱â¯2.0% and 71.5⯱â¯2.9% was released after 360â¯min (pHâ¯=â¯6.5) which reveals a potential anti-cancer activity in acidic environment. Cytotoxicity of TCIN in DMSO (0-50⯵M) was evaluated on MDCK and HeLa cell lines and exhibited low effect at either 24 or 48â¯h of exposure; whereas TCIN-loaded CSMP (0-50⯵M) showed, after 24â¯h of exposure, 67.6⯱â¯7.0 and 64.5⯱â¯3.9% cytotoxicity for MDCK and HeLa cell lines, respectively. At 48â¯h of exposure, TCIN-loaded CSMP achieved 81.1⯱â¯0.26 and 77.9⯱â¯4.2% cytotoxicity for MDCK and HeLa cell lines, respectively.
Assuntos
Acroleína/análogos & derivados , Antineoplásicos Fitogênicos/administração & dosagem , Quitosana/química , Microesferas , Acroleína/administração & dosagem , Acroleína/toxicidade , Animais , Antineoplásicos Fitogênicos/toxicidade , Proliferação de Células/efeitos dos fármacos , Reagentes de Ligações Cruzadas/química , Cães , Liberação Controlada de Fármacos , Células HeLa , Humanos , Hidrogéis/química , Células Madin Darby de Rim CaninoRESUMO
Many antineoplastic agents induce myelosuppression and leukopenia as secondary effects in patients. The development of anticancer agents that simultaneously provoke antitumor immune response represents an important therapeutic advance. The administration of 6-pentadecyl salicylic acid (6SA) contributes to the antitumor immunity using 4T1 breast cancer cells in Balb/c female mice, with Taxol as a positive control and in cotreatment with 6SA (6SA + Taxol; CoT). Our results show that 6SA reduces tumor volume and size by inducing caspase-8-mediated apoptosis without reducing tumor infiltrated lymphocytes. Also, 6SA reduced lung metastasis and increased the proportion of immune cells in blood, lymph nodes and bone marrow; more evidently, in the proportion of tumor-infiltrated natural killer (NK) cells and cytotoxic T lymphocytes. Taxol reduces helper and cytotoxic lymphocytes causing systemic immunosuppression and myelosuppression in bone marrow, whereas 6SA does not decrease any immune cell subpopulations in circulating blood and lymph nodes. More importantly, the CoT decreased the Taxol-induced cytotoxicity in circulating T cells and bone marrow. Treatment with 6SA increases the secretion of IL-2, IL-12, GM-CSF, TNF-α and IFN-γ and significantly reduces IL-10 and IL-17 secretion, suggesting that the reduction of regulatory T cells and tumor-associated macrophages contribute to the host control of tumor development. Finally, 6SA has an effective antineoplastic activity against breast cancer cells in an immunocompetent animal, reduces the myelosuppression and leukopenia that Taxol produces, improves the antitumoral immunological microenvironment and increases the overall survival of the animals improving the quality of life of patients with cancer.
Assuntos
Ácidos Anacárdicos/uso terapêutico , Antineoplásicos Fitogênicos/toxicidade , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Imunização/métodos , Paclitaxel/toxicidade , Ácidos Anacárdicos/farmacologia , Animais , Apoptose/imunologia , Neoplasias da Mama/sangue , Neoplasias da Mama/imunologia , Linhagem Celular Tumoral , Feminino , Imunidade Celular/efeitos dos fármacos , Imunidade Celular/fisiologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3HRESUMO
Paclitaxel (PTX) has a great clinical significance as an antitumor drug, although several side effects are strongly dose-limiting. In this way, we prepared a PTX-loaded 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy (polyethylene glycol)-2000] polymeric micelles (PM/PTX) in an attempt to improve safety and effectiveness of conventional PTX formulation (CrEL/EtOH/PTX). In this study, we evaluated from both formulations: stability after dilution, hemocompatibility, cellular uptake, acute toxicity in healthy mice, antitumor activity, and toxicity after multiple-dose treatment. PM/PTX appeared to be more stable than CrEL/EtOH/PTX after dilution. PM/PTX did not exhibit hemolytic activity (values <1%), even at high concentrations. In vitro cellular uptake study indicated that polymeric micelles were able to deliver more PTX (5.8 %) than CrEL/EtOH (2.7 %) to 4T1 cells. In the acute toxicity evaluation in healthy mice, CrEL/EtOH/PTX (single dose of 20 mg/kg) induced peripheral neuropathy, which was not observed in PM/PTX group. Similar results were observed after tumor-bearing mice received a multiple-dose regimen (seven doses of 10 mg/kg). Worth mentioning, we also evaluated vehicles, and CrEL/EtOH alone was not capable of inducing neuropathic pain. Besides, PM/PTX exhibited a higher antitumor activity with an inhibition ratio approximately 1.5-fold higher than CrEL/EtOH/PTX group. This study suggested that PM/PTX is safer than CrEL/EtOH/PTX, and was able to improve the antitumor effectiveness in a 4T1 breast cancer model.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Portadores de Fármacos/administração & dosagem , Micelas , Nanopartículas/administração & dosagem , Paclitaxel/administração & dosagem , Doenças do Sistema Nervoso Periférico/prevenção & controle , Animais , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/toxicidade , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Portadores de Fármacos/síntese química , Portadores de Fármacos/toxicidade , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/química , Nanopartículas/toxicidade , Paclitaxel/síntese química , Paclitaxel/toxicidade , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Polímeros/administração & dosagem , Polímeros/síntese química , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/fisiologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
The natural isomers of resveratrol, cis- and trans-resveratrol, are natural phenolic substances synthetized via the shikimate pathway and found in many sources, including grapes, peanuts, blackberries, pistachios, cacao, cranberries, and jackfruits. They have functional and pharmacological properties such as anticarcinogenic, antidiabetic, anti-inflammatory, and cardioprotective activities. The aim of this article is to review the data published on resveratrol and its isomers, and their biosynthesis in plants, food sources, health and toxic effects, and the excretion of their metabolites. Due to its contribution to the promotion of human health, it is convenient to gather more knowledge about its functional properties, food sources, and the interactions with the human body during the processes of eating, digestion, absorption, biotransformation, and excretion, to combine this information to improve the understanding of these substances.
Assuntos
Anti-Inflamatórios/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Fármacos Cardiovasculares/farmacologia , Alimentos , Hipoglicemiantes/farmacologia , Plantas/metabolismo , Resveratrol/farmacologia , Animais , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/toxicidade , Antineoplásicos Fitogênicos/metabolismo , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/toxicidade , Disponibilidade Biológica , Biotransformação , Fármacos Cardiovasculares/metabolismo , Fármacos Cardiovasculares/farmacocinética , Fármacos Cardiovasculares/toxicidade , Vias de Eliminação de Fármacos , Absorção Gastrointestinal , Humanos , Hipoglicemiantes/metabolismo , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/toxicidade , Isomerismo , Resveratrol/metabolismo , Resveratrol/farmacocinética , Resveratrol/toxicidadeRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Extracts, essential oils and molecules from Casearia sylvestris have popularly shown pharmacological actions against chronic diseases, as anxiety, inflammation, cancer and dyslipidemia. In the context of antitumoral therapy, we investigated in vitro, ex vivo and in vivo toxicological changes induced by a Fraction with Casearins (FC) and its component Casearin X isolated from C. sylvestris on animal and vegetal cells, and upon invertebrates and mammals. MATERIAL AND METHODS: Cytotoxicity was carried out using normal lines and absorbance and flow cytometry techniques, Artemia salina nauplii, Danio rerio embryos and meristematic cells from Allium cepa roots. Acute and 30 days-mice analysis were done by behavioral, hematological and histological investigations and DNA/chromosomal damages detected by alkaline Cometa and micronucleus assays. RESULTS: FC was cytotoxic against lung and fibroblasts cells and caused DNA breaks, loss of integrity and mitochondrial depolarization on ex vivo human leukocytes. It revealed 24 h-LC50 values of 48.8 and 36.7⯵g/mL on A. salina nauplii and D. rerio embryos, reduced mitotic index of A. cepa roots, leading to cell cycle arrest at metaphase and anaphase and micronuclei. FC showed i.p. and oral LD50 values of 80.9 and 267.1â¯mg/kg body weight. Subacute i.p. injections induced loss of weight, swelling of hepatocytes and tubules, tubular and glomerular hemorrhage, microvesicular steatosis, lung inflammatory infiltration, augment of GPT, decrease of albumin, alkaline phosphatase, glucose, erythrocytes, and lymphocytes, and neutrophilia (pâ¯>â¯0.05). FC-treated animals at 10â¯mg/kg/day i.p. caused micronuclei in bone marrow and DNA strand breaks in peripheral leukocytes. CONCLUSIONS: This research postulated suggestive side effects after use of FC-related drugs, demonstrating FC as antiproliferative and genotoxic on mammal and meristematic cells, including human leukocytes, teratogenicity upon zebrafish embryos, myelosuppression, clastogenicity, and morphological and biochemical markers indicating liver as main target for FC-induced systemic toxicity.
Assuntos
Antineoplásicos Fitogênicos/toxicidade , Casearia , Diterpenos Clerodânicos/toxicidade , Animais , Brasil , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cricetulus , Embrião não Mamífero/efeitos dos fármacos , Feminino , Fibroblastos/efeitos dos fármacos , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Medicina Tradicional , Meristema/citologia , Camundongos , Cebolas , Testes de Toxicidade , Peixe-ZebraRESUMO
To associate paclitaxel (PTX) with doxorubicin (DXR) is one of the main chemotherapy strategies for breast cancer (BC) management. Despite the high response rates for this combination, it presents a cardiotoxic synergism, attributed to pharmacokinetic interactions between PTX and both DXR and its metabolite, doxorubicinol. One of the main strategies to minimize the cardiotoxicity of the combination is to extend the interval of time between DXR and PTX administration. However, it has been previously suggested that their co-administration leads to better efficacy compared to their sequential administration. In the present study, we investigated different molar ratio combinations of PTX:DXR (10:1; 1:1, and 1:10) against the 4T1 murine breast cancer cell line and concluded that there is no benefit of enhancing PTX concentration above that of DXR on the combination. Therefore, we obtained a long-circulating and fusogenic liposomal formulation co-encapsulating PTX and DXR (LCFL-PTX/DXR) at a molar ratio of 1:10, respectively, which maintained the in vitro biological activity of the combination. This formulation was investigated for its antitumor activity and toxicity in Balb/c mice bearing 4T1 breast tumor, and compared to treatments with free PTX, free DXR, and the mixture of free PTX:DXR at 1:10 molar ratio. The higher tumor inhibition ratios were observed for the treatments with free and co-encapsulated PTX:DXR in liposomes (66.87 and 66.52%, respectively, P>0.05) as compared to the control. The great advantage of the treatment with LCFL-PTX/DXR was its improved cardiac toxicity profile. While degeneration was observed in the hearts of all animals treated with the free PTX:DXR combination, no signs of cardiac toxicity were observed for animals treated with the LCFL-PTX/DXR. Thus, LCFL-PTX/DXR enables the co-administration of PTX and DXR, and might be considered valuable for breast cancer management.
Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/administração & dosagem , Portadores de Fármacos/administração & dosagem , Paclitaxel/administração & dosagem , Animais , Antibióticos Antineoplásicos/toxicidade , Antineoplásicos Fitogênicos/toxicidade , Neoplasias da Mama/patologia , Cardiotoxicidade/patologia , Relação Dose-Resposta a Droga , Doxorrubicina/toxicidade , Portadores de Fármacos/toxicidade , Feminino , Humanos , Lipossomos , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Paclitaxel/toxicidade , Distribuição Aleatória , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/fisiologiaRESUMO
OBJECTIVES: Reported antioxidant, anti-inflammatory and neuroprotective properties for one aqueous-ethanolic extract from Thalassia testudinum which grows in the Caribbean Sea compelled us to explore about extract cytotoxic effects. METHODS: Cell viability was assayed on tumour (HepG2, PC12, Caco-2 and 4T1) and non-tumour (VERO, 3T3, CHO, MCDK and BHK2) cell lines. The extract effects upon primary cultures of rat and human hepatocytes and human lymphocytes were assayed. KEY FINDINGS: The extract exhibited cytotoxicity against cancer cells compared to normal cells, and the IC50 values were 102 µg/ml for HepG2, 135 µg/ml for PC12, 165 µg/ml for Caco-2 and 129 µg/ml for 4T1 cells after 48 h, whereas IC50 could not be calculated for normal cells. Additional data from a high-content screening multiparametric assay indicated that after 24-h exposure, the extract (up to 100 µg/ml) induced death in HepG2 cells through oxidative stress-associated mechanism, DNA damage and hypercalcaemia. Comet assay corroborated extract-induced DNA damage. CONCLUSIONS: Thalassia testudinum extract is more cytotoxic and produced more DNA damage on human hepatoma cells than to other non-tumour cells. A possible mechanism is suggested for extract-induced cytotoxicity based on oxidative stress, nuclear damage and hypercalcaemia in HepG2 cells. T. testudinum may be a source for antitumour agents.