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Melanoma is the most aggressive and lethal type of skin cancer due to its characteristics such as high metastatic potential and low response rate to existing treatment modalities. In this way, new drug prototypes are being studied to solve the problem of treating patients with melanoma. Among these, ruthenium-based metallopharmaceuticals may be promising alternatives due to their antitumor characteristics and low systemic toxicity. In this context, the present study evaluated the antineoplastic effect of the ruthenium complex [Ru(mtz)(dppe)2]PF6-2-mercaptothiazoline-di-1,2-bis(diphenylphosphine) ethaneruthenium(II), namely RuMTZ, on human melanoma (A-375) and murine (B16-F10) cells, considering different approaches. Through XTT colorimetric and clonogenic efficiency assays, the complex revealed the selective cytotoxic activity, with the lowest IC50 (0.4 µM) observed for A375 cells. RuMTZ also induced changes in cell morphology, increased cell population in the sub-G0 phase and inhibiting cell migration. The levels of γH2AX and cleaved caspase 3 proteins were increased in both cell lines treated with RuMTZ. These findings indicated that the cytotoxic activity of RuMTZ on melanoma cells is related, at least in part, to the induction of DNA damage and apoptosis. Therefore, RuMTZ exhibited promising antineoplastic activity against melanoma cells.
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Antineoplásicos , Complexos de Coordenação , Melanoma , Rutênio , Tiazolidinas , Humanos , Animais , Camundongos , Rutênio/farmacologia , Complexos de Coordenação/farmacologia , Melanoma/tratamento farmacológico , Ligantes , Antineoplásicos/farmacologia , Apoptose , Dano ao DNA , Linhagem Celular TumoralRESUMO
Melanoma, an aggressive and potentially fatal skin cancer, is constrained by immunosuppression, resistance, and high toxicity in its treatment. Consequently, there is an urgent need for innovative antineoplastic agents. Therefore, this study investigated the antimelanoma potential of guttiferone E (GE). In an allogeneic murine B16 melanoma model, GE was administered subcutaneously and intraperitoneally. Antitumor evaluation included tumor volume/weight measurements and histopathological and immunohistochemical analysis. Furthermore, the toxicity of the treatments was evaluated through body/organ weights, biochemical parameters, and genotoxicity. Subcutaneous administration of 20 mg/kg of GE resulted in a significant reduction in both tumor volume and weight, effectively suppressing melanoma cell proliferation as evidenced by a decrease in mitotic figures. The tumor growth inhibition rate was equivalent to 54%. This treatment upregulated cleaved caspase-3, indicating apoptosis induction. On the other hand, intraperitoneal administration of GE showed no antimelanoma effect. Remarkably, GE treatments exhibited no toxicity, evidenced by non-significant differences in body weight gain, as well as organ weight, biochemical parameters of nephrotoxicity and hepatotoxicity, and genotoxic damage. This study revealed, for the first time, the efficacy of subcutaneous administration of GE in reducing melanoma, in the absence of toxicity. Furthermore, it was observed that the apoptotic signaling pathway is involved in the antimelanoma property of GE. These findings offer valuable insights for further exploring GE's therapeutic applications in melanoma treatment.
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Melanoma Experimental , Camundongos Endogâmicos C57BL , Animais , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/patologia , Melanoma Experimental/metabolismo , Apoptose/efeitos dos fármacos , Camundongos , Masculino , Antineoplásicos/toxicidade , Antineoplásicos/administração & dosagem , Benzofenonas/farmacologia , Benzofenonas/administração & dosagem , Benzofenonas/toxicidade , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Proliferação de Células/efeitos dos fármacos , Carga Tumoral/efeitos dos fármacos , Linhagem Celular Tumoral , Injeções Subcutâneas , FemininoRESUMO
Melanoma is the most aggressive and lethal type of skin cancer, characterized by therapeutic resistance. In this context, the present study aimed to investigate the cytotoxic potential of manool, a diterpene from Salvia officinalis L., in human (A375) and murine (B16F10) melanoma cell lines. The analysis of cytotoxicity using the XTT assay showed the lowest IC50 after 48 h of treatment with the manool, being 17.6 and 18.2 µg/ml for A375 and B16F10, respectively. A selective antiproliferative effect of manool was observed on the A375 cells based on the colony formation assay, showing an IC50 equivalent to 5.6 µg/ml. The manool treatments led to 43.5% inhibition of the A375 cell migration at a concentration of 5.0 µg/ml. However, it did not affect cell migration in the B16F10 cells. Cell cycle analysis revealed that the manool interfered in the cell cycle of the A375 cells, blocking the G2/M phase. No changes in the cell cycle were observed in the B16F10 cells. Interestingly, manool did not induce apoptosis in the A375 cells, but apoptosis was observed after treatment of the B16F10 cells. Additionally, manool showed an antimelanoma effect in a reconstructed human skin model. Furthermore, in silico studies, showed that manool is stabilized in the active sites of the tubulin dimer with comparable energy concerning taxol, indicating that both structures can inhibit the proliferation of cancer cells. Altogether, it is concluded that manool, through the modulation of the cell cycle, presents a selective antiproliferative activity and a potential antimelanoma effect.
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Diterpenos , Melanoma , Neoplasias Cutâneas , Humanos , Animais , Camundongos , Linhagem Celular Tumoral , Melanoma/metabolismo , Diterpenos/farmacologia , Apoptose , Técnicas de Cultura de Células , Proliferação de CélulasRESUMO
Guttiferone E (GE) is a benzophenone found in Brazilian red propolis. In the present study, the effect of GE on human (A-375) and murine (B16-F10) melanoma cells was investigated. GE significantly reduced the cellular viability of melanoma cells in a time-dependent manner. In addition, GE demonstrated antiproliferative effect, with IC50 values equivalent to 9.0 and 6.6 µM for A-375 and B16-F10 cells, respectively. The treatment of A-375 cells with GE significantly increased cell populations in G0/G1 phase and decreased those in G2/M phase. Conversely, on B16-F10 cells, GE led to a significant decrease in the populations of cells in G0/G1 phase and concomitantly an increase in the population of cells in phase S. A significantly higher percentage of apoptotic cells was observed in A-375 (43.5%) and B16-F10 (49.9%) cultures after treatment with GE. Treatments with GE caused morphological changes and significant decrease to the melanoma cells' density. GE (10 µM) inhibited the migration of melanoma cells, with a higher rate of inhibition in B16-F10 cells (73.4%) observed. In addition, GE significantly reduced the adhesion of A375 cells, but showed no effect on B16-F10. Treatment with GE did not induce changes in P53 levels in A375 cultures. Molecular docking calculations showed that GE is stable in the active sites of the tubulin dimer with a similar energy to taxol chemotherapy. Taken together, the data suggest that GE has promising antineoplastic potential against melanoma.
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Antineoplásicos , Melanoma Experimental , Melanoma , Humanos , Animais , Camundongos , Linhagem Celular Tumoral , Proliferação de Células , Simulação de Acoplamento Molecular , Antineoplásicos/uso terapêutico , Benzofenonas/farmacologia , Benzofenonas/uso terapêutico , Melanoma/tratamento farmacológico , Melanoma Experimental/tratamento farmacológico , Camundongos Endogâmicos C57BLRESUMO
INTRODUCTION: Red propolis is synthetized from exudates of Dalbergia ecastophyllum (L) Taub. and Symphonia globulifera L.f., presents isoflavones, guttiferone E, xanthochymol, and oblongifolin B and has anti-inflammatory, antioxidant, and antiproliferative activities. OBJECTIVES: This study aimed to evaluate the antigenotoxic and anticarcinogenic potential of red propolis hydroalcoholic extract (RPHE) in rodents. METHODS: The influence of RPHE in doxorubicin (DXR)-induced genotoxicity was investigated through the micronucleus test in Swiss mice. Blood samples were also collected to investigate oxidative stress, hepatotoxicity, and nephrotoxicity. Was investigated the influence of RPHE in 1,2-dimethylhydrazine (DMH)-induced aberrant crypt foci, as well as its influence in proliferating cell nuclear antigen (PCNA) and the cyclooxygenase-2 (COX-2) expression in colon of rats, by immunohistochemistry. RESULTS: The results showed that RPHE (48 mg/kg) reduced DXR-induced genotoxicity. Animals treated with DXR showed significantly lower GSH serum levels in comparison to the negative control. RPHE treatments did not attenuated significantly the DXR-induced GSH depletion. No difference was observed in cytotoxicity parameters of mice hematopoietic tissues between the treatment groups, as well as the biochemical parameters of hepatotoxicity and nephrotoxicity. RPHE (12 mg/kg) reduced the DMH-induced carcinogenicity and toxicity, as well as DMH-induced PCNA and COX-2 expression in colon tissue. CONCLUSION: Therefore, was observed that the RPHE has chemopreventive effect, associated to antiproliferative and anti-inflammatory activities.
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This study explores the growth of bacterial, fungal, and interkingdom biofilms under aerobiosis or microaerobic conditions and the effect of ozonated sunflower oil on these biofilms. Candida species and Streptococcus mutans were used to study this interaction due to their importance in oral health and disease as these microorganisms display a synergistic relationship that manifests in the onset of caries and tooth decay. Biofilms were developed in a 96-well microtiter plate at 37ºC for 24 h, under aerobiosis or microaerobic conditions, and treated with ozonated oil for 5 to 120 min. All the microorganisms formed biofilms in both oxygenation conditions. Scanning electron microscopy was used to visualize biofilm morphology. Rodent experiments were performed to verify the oil-related toxicity and its efficacy in oral candidiasis. The growth of all Candida species was increased when co-cultured with S. mutans, whilst the growth of bacterium was greater only when co-cultured with C. krusei and C. orthopsilosis under aerobiosis and microaerobic conditions, respectively. Regardless of the oxygenation condition, ozonated oil significantly reduced the viability of all the tested biofilms and infected mice, showing remarkable microbicidal activity as corroborated with confocal microscopy and minimal toxicity. Thus, ozonated oil therapy can be explored as a strategy to control diseases associated with these biofilms especially in the oral cavity. LAY SUMMARY: We demonstrated that ozonated sunflower oil is effective at killing the biofilms formed by Candida species, by the bacterium Streptococcus mutans, or by both micoorganisms that can interact in the oral cavity, making it a potential therapeutic option for the treatment of these infections.
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Candida , Streptococcus mutans , Animais , Biofilmes , Candida albicans , Camundongos , Óleo de GirassolRESUMO
OBJECTIVES: Dalbergia ecastaphyllum (L.) Taub. is a semi-prostrate species associated with estuaries, mangroves and dunes. This plant species has great ecological and economic importance, especially concerning apiculture pasture and Brazilian red propolis production. In this study, non-clinical toxicological evaluations of the hydroalcoholic extract of D. ecastaphyllum stems (DEHE), the resin production source, were conducted. In addition, the action of DEHE on genomic instability and colon carcinogenesis was investigated. METHODS AND RESULTS: The extract's chemical profile was analysed by HPLC, and medicarpin, vestitol and neovestitol were found as major compounds. DEHE showed an IC50 equivalent to 373.2 µg/ml and LC50 equal 24.4 mg/L, when evaluated using the XTT colorimetric test and the zebrafish acute toxicity assay, respectively. DEHE was neither genotoxic nor cytotoxic at the highest dose, 2000 mg/kg, by peripheral blood micronucleus test. The treatments DEHE (6 and 24 mg/kg) led to the reduction of micronuclei induced by doxorubicin (DXR) in mice. Furthermore, significantly higher serum levels of reduced glutathione were observed in animals treated with DEHE plus DXR, revealing an antioxidant effect. Treatments with DEHE (48 mg/kg) led to a significant reduction in pre-neoplastic lesions induced by the 1,2-dimethylhydrazine (DMH) carcinogen in the rat colon. Immunohistochemical analysis revealed significantly lower levels of expression of COX-2 (86%) and PCNA (83%) in the colon of rats treated with DEHE plus DMH, concerning those treated with the carcinogen. CONCLUSIONS: These results indicate the involvement of anti-inflammatory and antiproliferative pathways in the protective effect of DEHE.
Assuntos
Dalbergia , Própole , Animais , Camundongos , Ratos , Brasil , Carcinógenos , Quimioprevenção , Dalbergia/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Própole/química , Própole/farmacologia , Peixe-ZebraRESUMO
Melanoma is the most aggressive type of skin cancer, and thus it is important to develop new drugs for its treatment. The present study aimed to examine the antitumor effects of solamargine a major alkaloid heteroside present in Solanum lycocarpum fruit. In addition solamargine was incorporated into nanoparticles (NP) of yttrium vanadate functionalized with 3-chloropropyltrimethoxysilane (YVO4:Eu3+:CPTES:SM) to determine antitumor activity. The anti-melanoma assessment was performed using a syngeneic mouse melanoma model B16F10 cell line. In addition, systemic toxicity, nephrotoxic, and genotoxic parameters were assessed. Solamargine, at doses of 5 or 10 mg/kg/day administered subcutaneously to male C57BL/6 mice for 5 days, decreased tumor size and frequency of mitoses in tumor tissue, indicative of a decrease in cell proliferation. Treatments with YVO4:Eu3+:CPTES:SM significantly reduced the number of mitoses in tumor tissue, associated with no change in tumor size. There were no apparent signs of systemic toxicity, nephrotoxicity, and genotoxicity initiated by treatments either with solamargine alone or plant alkaloid incorporated into NP. The animals treated with YVO4:Eu3+:CPTES:SM exhibited significant increase in spleen weight accompanied by no apparent histological changes in all tissues examined. In addition, animals treated with solamargine (10 mg/kg/day) and YVO4:Eu3+:CPTES:SM demonstrated significant reduction in hepatic DNA damage which was induced by tumor growth. Therefore, data suggest that solamargine may be considered a promising candidate in cancer therapy with no apparent toxic effects.
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Antineoplásicos/farmacologia , Melanoma Experimental/tratamento farmacológico , Alcaloides de Solanáceas/farmacologia , Animais , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Dano ao DNA , Fígado/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitose/efeitos dos fármacos , Nanopartículas/administração & dosagem , Silanos/química , Alcaloides de Solanáceas/toxicidade , Ítrio/químicaRESUMO
An alternative to reduce the undesirable effects of antineoplastic agents has been the combination of classical treatments with nutritional strategies aimed at reducing systemic toxicity without decreasing the antitumor activity of already used drugs. Within this context, this study evaluated the possible reduction of toxicity when cisplatin treatment is combined with watermelon pulp juice supplementation in C57BL/6 mice with melanoma. Watermelon is a fruit rich in vitamins, minerals, proteins, lycopene, carotene, and xanthophylls, which has shown effectiveness in the treatment of cardiovascular diseases, weight loss, urinary infections, gout, hypertension, and mutagenicity. The following parameters were analyzed: animal survival, bone marrow genotoxicity, serum creatinine and urea, histopathological features of the tumor tissue, tumor weight and volume, and weight of non-tumor tissues (kidney, liver, spleen, heart, and lung). The results showed that watermelon had no antitumor effect but reduced the toxicity of cisplatin, as demonstrated by an increase in the number of bone marrow cells and a decrease in serum creatinine and urea levels. The data suggest that watermelon pulp juice can be an alternative for reducing the side effects of antineoplastic agents.
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Antineoplásicos , Citrullus , Melanoma , Animais , Antineoplásicos/toxicidade , Cisplatino/toxicidade , Creatinina , Camundongos , Camundongos Endogâmicos C57BL , UreiaRESUMO
Abstract: Tradescantia pallida (Commelinaceae) has shown promising antibacterial, antioxidant and anticancer activities. This study aimed at extracting hexane from T. pallida (HE-TP) aerial parts to identify and quantify its volatile compounds by GC-MS and GC-FID and at evaluating its antifungal and antiproliferative activities. (E)-4-Methoxycynnamic acid (50.2%), 2,5-di-tert-butyl-1,4-benzoquinone (13.7%) and epijuvabione (10.4%) were the major components identified in HE-TP. HE-TP was incorporated into PDA medium, poured into Petri dishes and transferred to mycelial discs of pathogens. Percentages of inhibition of fungal growth were determined. HE-TP showed remarkable antifungal potential at the dose of 400 µL since it inhibited 100% of Penicillium digitatum and Sclerotinia sclerotiorum growth and 92.6% of Rhizopus stolonifer growth. Besides, HE-TP demonstrated cytotoxic activity against different human tumor cell lines with IC50 values between 231.43 and 428.76 µg/mL. Therefore, results showed that HE-TP has potential against fungi of agronomic interest and tumor cells.
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Abstract Adenocalymma axillarum (K.Schum.) L.G. Lohmann is a liana belonging to the family Bignoniaceae. In traditional medicine, the genus Adenocalymma is used to treat fever, skin ailments, and body, joint, and facial muscle pains, and it is also applied as cosmetic. Biological assays conducted with the A. axillarum crude leaf ethanol extract have indicated leishmanicidal activity and absence of cytotoxicity. This study aimed to analyze the A. axillarum leaf ethanol crude extract by high-performance liquid chromatography-high-resolution mass spectrometry- diode array detector (HPLC-HRMS-DAD) and to evaluate the leishmanicidal and cytotoxic activities of this crude extract, its fractions, and isolated compounds. HPLC-HRMS-DAD analysis of this extract revealed that it consisted mainly of flavonoids, with nine major compounds. Extract purification yielded 4-hydroxy-N-methylproline, 6-β-hydroxyipolamiide, quercetin-3-O-robinobioside, hyperin, isorhamnetin-3-O-robinobioside, and 3'-O-methylhyperin, which were identified by Nuclear Magnetic Resonance. The isolated compounds were inactive against Leishmania amazonensis promastigotes and human lung fibroblast cells.
Assuntos
Espectrometria de Massas/métodos , Espectroscopia de Ressonância Magnética/métodos , Cromatografia Líquida de Alta Pressão/métodos , Folhas de Planta/classificação , Misturas Complexas/química , Leishmania/classificação , Bignoniaceae/classificação , Articulações/anormalidadesRESUMO
The use of natural products as potential ligands has been explored as a strategy in the development of metal-based chemotherapy. Since ruthenium complexes are promising alternatives to traditional antitumor agents, this study evaluated the anti-melanoma potential of two ruthenium(II) complexes containing the naphthoquinone ligands lapachol (lap), [Ru(lap)(dppm)2]PF6, and lawsone (law), [Ru(law)(dppm)2]PF6, in addition to the bis(diphenylphosphino)methane (dppm) ligand, referred to as complexes (1) and (2), respectively, using a syngeneic murine melanoma model. Activation of the apoptotic pathway by the treatments was assessed by immunohistochemistry in tumor tissue. Additionally, toxicity of the treatments was evaluated by variation in body and organ weight, quantification of biochemical indicators of renal damage, and genotoxicity in bone marrow and hepatocytes. First, the antiproliferative activity of (1) and (2) was observed in B16F10 cells, with IC50 values of 2.78 and 1.68 µM, respectively. The results obtained in mice showed that, unlike complex (1), (2) possesses significant anti-melanoma activity demonstrated by a reduction in tumor volume and mass (88.42%), as well as in mitosis frequency (83.86%). Additionally, complex (2) increased the levels of cleaved caspase-3, inducing tumor cell apoptosis. When compared to the metallodrug cisplatin, complex (2) exhibited similar anti-melanoma activity and lower toxicity considering all parameters evaluated. In silico studies demonstrated no difference in the binding energy of the naphthoquinone complex between complexes (1) and (2). However, the complex containing the lawsone ligand has a lower molar volume, which may be important for interactions with minor DNA grooves. The present results demonstrate the antitumor efficiency of complex (2) and a significantly lower systemic toxicity compared to cisplatin.
Assuntos
Antineoplásicos/uso terapêutico , Complexos de Coordenação/uso terapêutico , Melanoma/tratamento farmacológico , Naftoquinonas/uso terapêutico , Fosfinas/uso terapêutico , Animais , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/toxicidade , Ligantes , Masculino , Camundongos Endogâmicos C57BL , Naftoquinonas/toxicidade , Fosfinas/toxicidade , Rutênio/química , Rutênio/toxicidadeRESUMO
Styrax camporum Pohl, a typical species from the Brazilian cerrado, commonly known as "benjoeiro", is used to treat gastroduodenal diseases. In previous studies carried out by our research group, hydroalcoholic extract of S. camporum stems (SCHE) exhibited antigenotoxic and antiproliferative effects. For a comparative analysis of the chemopreventive effect of SCHE, the aim of this study was to investigate the influence of SCHE against carcinogen 1,2-dimethylhydrazine (DMH)-induced DNA damage and pre-neoplastic lesions in Wistar rat colon. Animals were treated orally with SCHE at 250, 500 or 1000 mg/kg body weight in conjunction with a subcutaneous injection of DMH. DNA damage was assessed using the comet assay while tpre-neoplastic lesions by aberrant crypt foci (ACF) assay. The following hepatic oxidative stress markers were determined including activities of catalase (CAT) and glutathione S-transferase (GST) as well as levels of reduced glutathione (GSH) and malondialdehyde (MDA). Treatment with SCHE was not genotoxic or carcinogenic at the highest dose tested (1000 mg/kg b.w.). The extract effectively inhibited DNA damage and pre-neoplastic lesions induced by DMH administration at all concentrations tested. Measurement of CAT, and GST activities and levels of GSH showed that SCHE did not reduce oxidative processes. In contrast, treatment with SCHE (1000 mg/kg b.w.) decreased liver MDA levels. Taken together, these findings suggested the chemopreventive effect attributed to SCHE in colon carcinogenesis, may be related to its capacity to inhibit DNA damage as well as an antioxidant action associated with its chemical constituents egonol and homoegonol.
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Anticarcinógenos/farmacologia , Dano ao DNA/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Styrax/química , Animais , Carcinógenos/farmacologia , Carcinógenos/toxicidade , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Ensaio Cometa , Dimetilidrazinas/farmacologia , Dimetilidrazinas/toxicidade , Masculino , Extratos Vegetais/química , Caules de Planta/química , Substâncias Protetoras/química , Ratos , Ratos WistarRESUMO
Copaifera langsdorffii Desf. is a plant found in South America, especially in Brazil. Oleoresin and the leaves of this plant is used as a popular medicinal agent. However, few studies on the chemical composition of aerial parts and related biological activities are known. This study aimed to examine the cytotoxic, genotoxic, and antigenotoxic potential of C. langsdorffii aerial parts hydroalcoholic extract (CLE) and two of its major compounds afzelin and quercitrin. The cytotoxic and antigenotoxic potential of CLE was determined as follows: 1) against genotoxicity induced by doxorubicin (DXR) or methyl methanesulfonate (MMS) in V79 cells; 2) by direct and indirect-acting mutagens in Salmonella typhimurium strains; and 3) by MMS in male Swiss mice. The protective effects of afzelin and quercitrin against DXR or MMS were also evaluated in V79 and HepG2 cells. CLE was cytotoxic as evidenced by clonogenic efficiency assay. Further, CLE did not induce a significant change in frequencies of chromosomal aberrations and micronuclei; as well as number of revertants in the Ames test demonstrating absence of genotoxicity. In contrast, CLE was found to be antigenotoxic in mammalian cells. The results also showed that CLE exerted inhibitory effect against indirect-acting mutagens in the Ames test. Afzelin and quercitrin did not reduce genotoxicity induced by DXR or MMS in V79 cells. However, treatments using afzelin and quercitrin decreased MMS-induced genotoxicity in HepG2 cells. The antigenotoxic effect of CLE observed in this study may be partially attributed to the antioxidant activity of the combination of major components afzelin and quercitrin.
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Dano ao DNA/efeitos dos fármacos , Fabaceae/química , Manosídeos/farmacologia , Extratos Vegetais/farmacologia , Proantocianidinas/farmacologia , Substâncias Protetoras/farmacologia , Quercetina/análogos & derivados , Animais , Doxorrubicina/toxicidade , Células Hep G2 , Humanos , Masculino , Metanossulfonato de Metila/toxicidade , Camundongos , Mutagênicos/farmacologia , Mutagênicos/toxicidade , Extratos Vegetais/química , Folhas de Planta/química , Quercetina/farmacologia , Salmonella typhimurium/efeitos dos fármacosRESUMO
The present study aimed to evaluate the effect of the manool diterpene on genomic integrity. For this purpose, we evaluated the influence of manool on genotoxicity induced by mutagens with different mechanisms of action, as well as on colon carcinogenesis. The results showed that manool (0.5 and 1.0 µg/ml) significantly reduced the frequency of micronuclei induced by doxorubicin (DXR) and hydrogen peroxide in V79 cells but did not influence genotoxicity induced by etoposide. Mice receiving manool (1.25 mg/kg) exhibited a significant reduction (79.5%) in DXR-induced chromosomal damage. The higher doses of manool (5.0 and 20 mg/kg) did not influence the genotoxicity induced by DXR. The anticarcinogenic effect of manool (0.3125, 1.25 and 5.0 mg/kg) was also observed against preneoplastic lesions chemically induced in rat colon. A gradual increase in manool doses did not cause a proportional reduction of preneoplastic lesions, thus demonstrating the absence of a dose-response relationship. The analysis of serum biochemical indicators revealed the absence of hepatotoxicity and nephrotoxicity of treatments. To explore the chemopreventive mechanisms of manool via anti-inflammatory pathways, we evaluated its effect on nitric oxide (NO) production and on the expression of the NF-kB gene. At the highest concentration tested (4 µg/ml), manool significantly increased NO production when compared to the negative control. On the other hand, in the prophylactic treatment model, manool (0.5 and 1.0 µg/ml) was able to significantly reduce NO levels produced by macrophages stimulated with lipopolysaccharide. Analysis of NF-kB in hepatic and renal tissues of mice treated with manool and DXR revealed that the mutagen was unable to stimulate expression of the gene. In conclusion, manool possesses antigenotoxic and anticarcinogenic effects and its anti-inflammatory potential might be related, at least in part, to its chemopreventive activity.
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Anticarcinógenos/farmacologia , Neoplasias do Colo/tratamento farmacológico , Dano ao DNA/efeitos dos fármacos , Diterpenos/farmacologia , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Lesões Pré-Cancerosas/tratamento farmacológico , Animais , Anticarcinógenos/química , Linhagem Celular , Neoplasias do Colo/induzido quimicamente , Cricetinae , Modelos Animais de Doenças , Diterpenos/química , Relação Dose-Resposta a Droga , Doxorrubicina/efeitos adversos , Etoposídeo/efeitos adversos , Peróxido de Hidrogênio/efeitos adversos , Masculino , Camundongos , Micronúcleos com Defeito Cromossômico/induzido quimicamente , Testes para Micronúcleos , Testes de Mutagenicidade , Extratos Vegetais/farmacologia , Lesões Pré-Cancerosas/induzido quimicamente , Ratos , Ratos Wistar , Salvia officinalis/químicaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Jarilla is the common name of an appreciated group of native plants from the semi-arid region in Argentina (Larrea cuneifolia Cav., Larrea divaricata Cav. and Zuccagnia punctata Cav.) that have been historically consumed to heal respiratory, musculoskeletal and skin ailments, as well as recommended for weakness/tiredness, hypertension, diabetes and cancer treatment. It was previously reported that some biological properties could be improved when these plants are used jointly. Infusions of a defined mixture, composed by three Jarilla species, L. cuneifolia: L. divaricata: Z. punctata (0.5:0.25:0.25) (HM2) showed synergistic and additive effect on antioxidant activity even after passing through the gastro-duodenal tract. AIM OF THE STUDY: The main purpose of this work was to evaluate antigenotoxic, antitumor, and anti-metastatic properties of the Jarilla species that grow in the Northwest of Argentina and a herbal combination of them. MATERIAL AND METHODS: Infusions of Jarilla mixture (HM2), and of each single plant species were prepared. Phenolic profiles of infusions were analyzed by HPLC-ESI-MS/MS and two relevant chemical markers were quantified. The antigenotoxic activity was evaluated by using the Ames test and the Cytokinesis-Block Micronucleus (CBMN) assay against direct mutagens. Evaluations of both cytotoxicity and antiproliferative effects were conducted on tumor and non-tumor cell lines. Both in vivo tumoral growth and metastasis inhibition were evaluated by using a carcinoma model on Balb/c mice. RESULTS: HM2 mix could suppress genetic and chromosome mutations induced by 4-nitro-o-phenylendiamine (4-NPD) and doxorubicin. Herbal mixture and single plant infusions showed cytotoxic effect against mammary, uterus, and brain tumoral cells without a selective action vs normal human cell line. HM2 mix was able to reduce mammary tumor mass on the Balb/c mice model and showed a significant reduction in the number of metastatic nodules in the lungs. CONCLUSIONS: Our results suggest that the combinations of three Jarilla species from northwest Argentina would be a promising alternative to treat or slow down the development of chronic diseases, such as cancer.
Assuntos
Antimutagênicos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Fabaceae , Larrea , Neoplasias/tratamento farmacológico , Extratos Vegetais/farmacologia , Animais , Antimutagênicos/isolamento & purificação , Antineoplásicos Fitogênicos/isolamento & purificação , Argentina , Células CHO , Cricetulus , Fabaceae/química , Células HeLa , Humanos , Larrea/química , Células MCF-7 , Masculino , Medicina Tradicional , Camundongos Endogâmicos BALB C , Metástase Neoplásica , Neoplasias/patologia , Fitoterapia , Extratos Vegetais/isolamento & purificação , Plantas MedicinaisRESUMO
Licochalcone A (LicoA) is a flavonoid derived from Glycyrrhiza spp. plants. The present study aimed to investigate the antioxidant, cytotoxic, genotoxic, and chemopreventive effects of LicoA in in vitro and in vivo systems. The results showed that LicoA (197.1 µM) scavenged 77.92% of free radicals. Concentrations of 147.75 µM or higher LicoA produced cytotoxicity in Chinese hamster ovary (CHO) fibroblasts. LicoA treatments of 4.43 to 10.34 µM did not exert genotoxic activity, but at 11.8 µM significantly lowered nuclear division indexes, compared to negative control, revealing cytotoxicity. Lower concentrations (1.85 to 7.39 µM) exhibited protective activity against chromosomal damage induced by doxorubicin (DXR) or methyl methanesulfonate (MMS) in CHO cells. LicoA exerted no marked influence on DXR-induced genotoxicity in mouse erythrocytes, but reduced pre-neoplastic lesions induced by 1,2-dimethylhydrazine (DMH) in rat colon at 3.12 to 50 mg/kg b.w. Biochemical markers and body weight indicated no apparent toxicity. These findings contribute to better understanding the mechanisms underlying LicoA-initiated activity as a promising chemopreventive compound. ABBREVIATIONS: AC, aberrant crypts; ACF, aberrant crypt foci; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BOD, biochemical oxygen demand; CHO, Chinese hamster ovary fibroblast; DMH, 1,2-dimethylhydrazine; DMSO, dimethyl sulfoxide; DPPH, 2,2-diphenyl-1-picrylhydrazyl; DXR, doxorubicin hydrochloride; EDTA, ethylenediaminetetraacetic acid; GA, gallic acid; LicoA, licochalcone A; MMS, methyl methanesulfonate; MNBC, micronucleated binucleated cells; MNPCE, micronucleated polychromatic erythrocyte; NCE, normochromatic erythrocyte; NDI, nuclear division index; PBS, phosphate-buffered saline; PCE, polychromatic erythrocyte; XTT, 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide.
Assuntos
Antioxidantes/farmacologia , Chalconas/farmacologia , Citotoxinas/farmacologia , Mutagênicos/farmacologia , Substâncias Protetoras/farmacologia , Animais , Masculino , CamundongosRESUMO
Melanoma is the deadliest type of skin cancer. Treatments that directly address tumor survival are required. Indomethacin (IND) is a well-known drug used worldwide. Although widely used as a therapeutic agent, IND has undesirable gastrointestinal effects. PURPOSE: To investigate the antitumor efficacy of IND incorporated into mesoporous silica nanoparticles (MSNPs+IND), as well as its toxic potential in a syngeneic murine B16 melanoma model. METHODS: Antitumor activity was evaluated by measuring tumor size and weight and by histopathological analysis. Possible molecular signaling pathways involved in the antitumor activity were analyzed by Western blot in liver tissue and by immunohistochemistry in tumor tissue. The potential toxicity was evaluated by determining body and organ weights and by biochemical and genotoxic analysis. RESULTS: MSNPs+IND treatments inhibited tumor growth by up to 70.09% and decreased the frequency of mitosis in tumor tissues, which was up to 37.95% lower compared to the IND groups. In hepatic tissue, COX-2 levels decreased significantly after treatment with MSNPs+IND and IND. Additionally, MSNPs+IND and IND increased the levels of cleaved caspase-3 (156.25% and 137.50%, respectively), inducing tumor cell apoptosis. Genotoxicity was limited to the group treated with the higher concentration of IND, while MSNPs prevented IND-induced genotoxicity. CONCLUSIONS: MSNPs may be promising for future applications in cancer therapy.
Assuntos
Antineoplásicos/administração & dosagem , Indometacina/administração & dosagem , Melanoma/tratamento farmacológico , Nanopartículas/química , Animais , Antineoplásicos/farmacologia , Caspase 3/metabolismo , Linhagem Celular Tumoral , Ciclo-Oxigenase 2/metabolismo , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Indometacina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitose/efeitos dos fármacos , Porosidade , Dióxido de Silício/químicaRESUMO
Betulinic acid (BA) is a pentacyclic triterpenoid found in several plant species. Urethane (URE) is a known promutagen. Here, we examine the genotoxicity and mutagenicity of BA alone or in combination with URE using the bone marrow micronucleus assay in mice bone marrow cells and the Somatic Mutation and Recombination Test in Drosophila melanogaster. Findings revealed that BA alone was not genotoxic, but reduced the frequency of micronucleus when compared to the positive control. No significant differences were observed in the cytotoxicity. Biochemical analyzes showed no significant differences for liver (AST and ALT) or renal (creatinine and urea) function parameters, indicating the absence of hepatotoxic and nephrotoxic effects. BA alone did not increase the frequency of mutant spots, but reduced the total frequency of mutant spots when co-administered with URE in both ST and HB crosses. In addition, BA reduced the recombinogenic effect of URE at the highest concentrations of both crosses. In conclusion, under experimental conditions, BA has modulatory effects on the genotoxicity induced by URE in mice, as well as in somatic cells of D. melanogaster. We suggest that the modulatory effects of BA may be mainly due to its antioxidant and apoptotic properties.
Assuntos
Drosophila melanogaster/efeitos dos fármacos , Mutagênese/efeitos dos fármacos , Triterpenos/farmacologia , Uretana/toxicidade , Animais , Antimutagênicos/farmacologia , Antioxidantes/farmacologia , Medula Óssea/efeitos dos fármacos , Carcinógenos/farmacologia , Drosophila melanogaster/genética , Feminino , Cabelo/efeitos dos fármacos , Masculino , Camundongos , Testes de Mutagenicidade , Triterpenos Pentacíclicos , Taxa de Sobrevida , Tricomas/efeitos dos fármacos , Triterpenos/química , Asas de Animais/efeitos dos fármacos , Ácido BetulínicoRESUMO
Abstract Propolis is a resinous substance collected and processed by Apis mellifera from parts of plants, buds and exudates. In Minas Gerais (MG) state, Brazil, green propolis is produced from the collection of resinous substance found in shoot apices of Baccharis dracunculifolia. This paper aims to investigate the chemical composition and in vitro antioxidant, anti-Helicobacter pylori, antimycobacterial and antiproliferative activities of essential oil (EO) from Brazilian green propolis (BGP-EO). The oil showed high antibacterial activity against H. pylori (MIC = 6.25 µg/mL), Mycobacterium avium (MIC = 62.5 µg/mL) and M. tuberculosis (MIC = 64 µg/mL). Its antioxidant activity was evaluated in vitro by both DPPH (IC50 = 23.48 µg/mL) and ABTS (IC50 = 32.18 µg/mL) methods. The antiproliferative activity in normal (GM07492A, lung fibroblasts) and tumor cell lines (MCF-7, HeLa and M059J) was analyzed by the XTT assay. BGP-EO showed inhibition of normal cell growth at 68.93 ± 2.56 µg/mL. Antiproliferative activity was observed against human tumor cell lines, whose IC50 values were 56.17, 66.43 and -65.83 µg/mL for MCF-7, HeLa and M059J cells, respectively. Its major constituents, which were determined by GC-FID and GC-MS, were carvacrol (20.7 %), acetophenone (13.5 %), spathulenol (11.0 %), (E)-nerolidol (9.7 %) and β-caryophyllene (6.2 %). These results showed the effectiveness of BGP-EO as a natural product which has promising biological activities.