RESUMO
The steroidal alkaloid tomatidine is an aglycone of α-tomatine, which is abundant in tomato leaves and has several biological activities. Tomatidine has been reported to inhibit the growth of cultured cancer cells in vitro, but its anti-cancer activity in vivo and inhibitory effect against gastric cancer cells remain unknown. We investigated the efficacy of tomatidine using human gastric cancer-derived 85As2 cells and its tumor-bearing mouse model and evaluated the effect of tomatidine-rich tomato leaf extract (TRTLE) obtained from tomato leaves. In the tumor-bearing mouse model, tumor growth was significantly inhibited by feeding a diet containing tomatidine and TRTLE for 3 weeks. Tomatidine and TRTLE also inhibited the proliferation of cultured 85As2 cells. Microarray data of gene expression analysis in mouse tumors revealed that the expression levels of mRNAs belonging to the type I interferon signaling pathway were altered in the mice fed the diet containing tomatidine and TRTLE. Moreover, the knockdown of one of the type I interferon-stimulated genes (ISGs), interferon α-inducible protein 27 (IFI27), inhibited the proliferation of cultured 85As2 cells. This study demonstrates that tomatidine and TRTLE inhibit the tumor growth in vivo and the proliferation of human gastric cancer-derived 85As2 cells in vitro, which could be due to the downregulation of ISG expression.
Assuntos
Alcaloides , Solanum lycopersicum , Neoplasias Gástricas , Alcaloides/metabolismo , Alcaloides/farmacologia , Animais , Humanos , Interferons , Camundongos , Extratos Vegetais/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Tomatina/análogos & derivadosRESUMO
The steroidal glycoalkaloid α-tomatine (αTM) and its aglycone tomatidine (TD) are abundant in the skin of unripe green tomato and present in tomato leaves and flowers. They mainly serve as defensive agents to protect the plant against infections by insects, bacteria, parasites, viruses, and fungi. In addition, the two products display a range of pharmacological properties potentially useful to treat various human diseases. We have analyzed all known pharmacological activities of αTM and TD, and the corresponding molecular targets and pathways impacted by these two steroidal alkaloids. In experimental models, αTM displays anticancer effects, particularly strong against androgen-independent prostate cancer, as well as robust antifungal effects. αTM is a potent cholesterol binder, useful as a vaccine adjuvant to improve delivery of protein antigens or therapeutic oligonucleotides. TD is a much less cytotoxic compound, able to restrict the spread of certain viruses (such as dengue, chikungunya and porcine epidemic diarrhea viruses) and to provide cardio and neuro-protective effects toward human cells. Both αTM and TD exhibit marked anti-inflammatory activities. They proceed through multiple signaling pathways and protein targets, including the sterol C24 methyltransferase Erg6 and vitamin D receptor, both directly targeted by TD. αTM is a powerful regulator of the NFkB/ERK signaling pathway implicated in various diseases. Collectively, the analysis shed light on the multitargeted action of αTM/TD and their usefulness as chemo-preventive or chemotherapeutic agents. A novel medicinal application for αTM is proposed.
Assuntos
Anti-Infecciosos/farmacologia , Anti-Inflamatórios/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Antiparasitários/farmacologia , Inseticidas/farmacologia , Solanum lycopersicum/química , Anti-Infecciosos/química , Anti-Infecciosos/isolamento & purificação , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antiparasitários/química , Antiparasitários/isolamento & purificação , Humanos , Inseticidas/química , Inseticidas/isolamento & purificação , Conformação Molecular , Tomatina/análogos & derivados , Tomatina/química , Tomatina/isolamento & purificação , Tomatina/farmacologiaRESUMO
Targeting the autophagy process is considered to be a promising new strategy for drug treatment of ovarian cancer. α-Tomatine, a steroidal alkaloid extracted, is mainly isolated from leaves, roots and immature green tomatoes. α-Tomatine has biological activities such as anticancer, antioxidative and anti-inflammatory. The study aimed to explore the effects of α-tomatine on proliferation, apoptosis and autophagy and the underlying mechanisms in ovarian cancer Skov3 cells. After treatment with different concentrations of α-tomatine (0, 0.75, 1 and 1.5 µM) in Skov3 cells for 24 h, proliferation was determined by the CCK-8 assay, and apoptosis was detected by flow cytometric analysis. Autophagy in cells was determined by the number of fluorescent spots using confocal fluorescence microscopy after mRFP-GFP-LC3 transfection. The relationship between autophagy and apoptosis was proved by Beclin-1 overexpression. The protein expression levels were tested by western blotting. The results demonstrated that α-tomatine effectively repressed proliferation, exerted a proapoptotic effect and inhibited early-stage autophagy in Skov3 cells in a dose- and time-dependent manner. Additionally, Beclin-1 overexpression significantly suppressed α-tomatine-treated apoptosis in Skov3 cells, indicating that α-tomatine inhibits autophagy to induce apoptosis. We also found α-tomatine inhibited the protein expression levels of PI3K/Akt/mTOR signaling pathway. However, the autophagy inhibition of α-tomatine could be reversed obviously by Beclin-1 overexpression. Taken together, α-tomatine inhibited autophagy through Beclin-1. Our study suggests that α-tomatine, as a novel early-stage autophagy inhibitor, might be a potential drug for further treatment of ovarian cancer by inhibiting proliferation and promoting apoptosis.
Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Proteína Beclina-1/metabolismo , Tomatina/análogos & derivados , Linhagem Celular Tumoral , Feminino , Humanos , Solanum lycopersicum/química , Estrutura Molecular , Neoplasias Ovarianas/tratamento farmacológico , Transdução de Sinais , Tomatina/farmacologiaRESUMO
Potato (Solanum tuberosum), a worldwide major food crop, produces the toxic, bitter tasting solanidane glycoalkaloids α-solanine and α-chaconine. Controlling levels of glycoalkaloids is an important focus on potato breeding. Tomato (Solanum lycopersicum) contains a bitter spirosolane glycoalkaloid, α-tomatine. These glycoalkaloids are biosynthesized from cholesterol via a partly common pathway, although the mechanisms giving rise to the structural differences between solanidane and spirosolane remained elusive. Here we identify a 2-oxoglutarate dependent dioxygenase, designated as DPS (Dioxygenase for Potato Solanidane synthesis), that is a key enzyme for solanidane glycoalkaloid biosynthesis in potato. DPS catalyzes the ring-rearrangement from spirosolane to solanidane via C-16 hydroxylation. Evolutionary divergence of spirosolane-metabolizing dioxygenases contributes to the emergence of toxic solanidane glycoalkaloids in potato and the chemical diversity in Solanaceae.
Assuntos
Vias Biossintéticas , Dioxigenases/biossíntese , Dioxigenases/genética , Solanum tuberosum/enzimologia , Solanum tuberosum/genética , Sequência de Aminoácidos , Vias Biossintéticas/genética , Colesterol/metabolismo , Regulação da Expressão Gênica de Plantas , Genes de Plantas/genética , Hidroxilação , Ácidos Cetoglutáricos/metabolismo , Solanum lycopersicum/enzimologia , Solanum lycopersicum/genética , Filogenia , Plantas Geneticamente Modificadas , Metabolismo Secundário/genética , Metabolismo Secundário/fisiologia , Solanina/análogos & derivados , Solanum melongena/enzimologia , Solanum melongena/genética , Tomatina/análogos & derivados , Tomatina/metabolismoRESUMO
Porcine epidemic diarrhea virus (PEDV) causes lethal diarrhea in suckling piglets, leading to severe economic losses worldwide. There is an urgent need to find new therapeutic methods to prevent and control PEDV. Not only is there a shortage of commercial anti-PEDV drugs, but available commercial vaccines fail to protect against highly virulent PEDV variants. We screened an FDA-approved library of 911 natural products and found that tomatidine, a steroidal alkaloid extracted from the skin and leaves of tomatoes, demonstrates significant inhibition of PEDV replication in Vero and IPEC-J2 cells in vitro. Molecular docking and molecular dynamics analysis predicted interactions between tomatidine and the active pocket of PEDV 3CL protease, which were confirmed by fluorescence spectroscopy and isothermal titration calorimetry (ITC). The inhibiting effect of tomatidine on 3CL protease was determined using cleavage visualization and FRET assay. Tomatidine-mediated blocking of 3CL protease activity in PEDV-infected cells was examined by western blot detection of the viral polyprotein in PEDV-infected cells. It indicates that tomatidine inhibits PEDV replication mainly by targeting 3CL protease. In addition, tomatidine also has antiviral activity against transmissible gastroenteritis virus (TGEV), porcine reproductive and respiratory syndrome virus (PRRSV), encephalo myocarditis virus (EMCV) and seneca virus A (SVA) in vitro. These results may be helpful in developing a new prophylactic and therapeutic strategy against PEDV and other swine disease infections.
Assuntos
Antivirais/farmacologia , Vírus da Diarreia Epidêmica Suína/fisiologia , Tomatina/análogos & derivados , Proteínas Virais/metabolismo , Replicação Viral/efeitos dos fármacos , Antivirais/química , Peptídeo Hidrolases/metabolismo , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Vírus da Diarreia Epidêmica Suína/efeitos dos fármacos , Vírus da Diarreia Epidêmica Suína/enzimologia , Tomatina/química , Tomatina/farmacologia , Replicação Viral/fisiologiaRESUMO
Although drug therapies are available for postmenopausal osteoporosis, these drugs are not free of side effects and long-term adherence to them are low. A safe and effective nutritional approach to counter postmenopausal osteoporosis is an important research goal. We fed ovariectomized (OVX) Sprague-Dawley rats a diet supplemented with 1% or 2% green tomato extract (GTE). After 12 weeks, micro-computed tomography scans revealed that GTE supplementation effectively prevented distal femur bone loss. This prevention was due to improved bone formation and suppressed bone resorption as observed by the regulation of osteoblast and osteoclast activities. GTE supplementation also improved bone formation through Bmp2-Smad 1/5/8-Runx2 signaling, while bone resorption was regulated by the receptor activator of nuclear factor kappa-B (RANKL)/osteoprogeterin (OPG) pathway. These results suggest that GTE supplementation prevents severe postmenopausal bone loss by maintaining the regulation of bone homeostasis in OVX rats. GTE as a diet supplement might be a potential novel alternative for the prevention of postmenopausal osteoporosis.
Assuntos
Osteoporose Pós-Menopausa/prevenção & controle , Extratos Vegetais/uso terapêutico , Solanum lycopersicum , Animais , Densidade Óssea/efeitos dos fármacos , Proteína Morfogenética Óssea 2/metabolismo , Reabsorção Óssea/prevenção & controle , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Solanum lycopersicum/química , Osteogênese/efeitos dos fármacos , Osteoprotegerina/metabolismo , Ovariectomia , Fitoterapia , Ligante RANK/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Proteínas Smad Reguladas por Receptor/metabolismo , Tomatina/análogos & derivados , Tomatina/análise , Aumento de PesoRESUMO
Thousands of specialized, steroidal metabolites are found in a wide spectrum of plants. These include the steroidal glycoalkaloids (SGAs), produced primarily by most species of the genus Solanum, and metabolites belonging to the steroidal saponins class that are widespread throughout the plant kingdom. SGAs play a protective role in plants and have potent activity in mammals, including antinutritional effects in humans. The presence or absence of the double bond at the C-5,6 position (unsaturated and saturated, respectively) creates vast structural diversity within this metabolite class and determines the degree of SGA toxicity. For many years, the elimination of the double bond from unsaturated SGAs was presumed to occur through a single hydrogenation step. In contrast to this prior assumption, here, we show that the tomato GLYCOALKALOID METABOLISM25 (GAME25), a short-chain dehydrogenase/reductase, catalyzes the first of three prospective reactions required to reduce the C-5,6 double bond in dehydrotomatidine to form tomatidine. The recombinant GAME25 enzyme displayed 3ß-hydroxysteroid dehydrogenase/Δ5,4 isomerase activity not only on diverse steroidal alkaloid aglycone substrates but also on steroidal saponin aglycones. Notably, GAME25 down-regulation rerouted the entire tomato SGA repertoire toward the dehydro-SGAs branch rather than forming the typically abundant saturated α-tomatine derivatives. Overexpressing the tomato GAME25 in the tomato plant resulted in significant accumulation of α-tomatine in ripe fruit, while heterologous expression in cultivated eggplant generated saturated SGAs and atypical saturated steroidal saponin glycosides. This study demonstrates how a single scaffold modification of steroidal metabolites in plants results in extensive structural diversity and modulation of product toxicity.
Assuntos
Alcaloides/biossíntese , Saponinas/biossíntese , Solanaceae/química , Alcaloides/química , Regulação da Expressão Gênica de Plantas/genética , Glicosídeos/biossíntese , Glicosídeos/química , Solanum lycopersicum/enzimologia , Solanum lycopersicum/genética , Solanum lycopersicum/metabolismo , Oxirredutases/metabolismo , Extratos Vegetais/química , Plantas Geneticamente Modificadas/metabolismo , Saponinas/química , Saponinas/metabolismo , Solanaceae/metabolismo , Esteroides/química , Tomatina/análogos & derivados , Tomatina/metabolismoRESUMO
SCOPE: Diets rich in tomato products are associated with a reduced risk of various chronic disease processes. The carotenoid lycopene is most intensely studied as the bioactive mediating health effects, yet tomatoes contain an array of phytochemicals. An untargeted metabolomics study is conducted on blood plasma to identify novel markers of tomato consumption absorbed from the diet and released into the bloodstream in mice. METHODS AND RESULTS: Male mice are fed a control AIN-93G diet or the same diet supplemented with 0.25 % lycopene beadlets, or 10 % freeze-dried red tomato, tangerine tomato, or low-carotenoid tomato for 4 weeks. Untargeted UHPLC-QTOF-MS data acquisition and differential analysis of plasma metabolites reveals several structurally related deglycosylated tomato steroidal alkaloids, including tomatidine and hydroxylated/desaturated derivatives, in plasma after the consumption of all three tomato varieties. Additionally, plasma metabolite profiles reflect glycoalkaloid forms found in the tomato diets. CONCLUSION: Dietary tomato glycoalkaloids are cleaved during digestion to aglycones and further metabolized post-absorption. Steroidal alkaloids in plasma may serve as novel and specific biomarkers of tomato consumption and represent a class of phytochemical metabolites that could potentially have in vivo bioactivity impacting health and disease processes.
Assuntos
Alcaloides/sangue , Metabolômica/métodos , Solanum lycopersicum , Animais , Biomarcadores/sangue , Peso Corporal , Carotenoides/farmacologia , Cromatografia Líquida de Alta Pressão/métodos , Suplementos Nutricionais , Licopeno , Solanum lycopersicum/química , Masculino , Espectrometria de Massas/métodos , Camundongos Endogâmicos C57BL , Tomatina/análogos & derivados , Tomatina/sangueRESUMO
Candida albicans is a major cause of fungal diseases in humans, and its resistance to available drugs is of concern. In an attempt to identify novel antifungal agents, we initiated a small-scale screening of a library of 199 natural plant compounds (i.e., natural products [NPs]). In vitro susceptibility profiling experiments identified 33 NPs with activity against C. albicans (MIC50s ≤ 32 µg/ml). Among the selected NPs, the sterol alkaloid tomatidine was further investigated. Tomatidine originates from the tomato (Solanum lycopersicum) and exhibited high levels of fungistatic activity against Candida species (MIC50s ≤ 1 µg/ml) but no cytotoxicity against mammalian cells. Genome-wide transcriptional analysis of tomatidine-treated C. albicans cells revealed a major alteration (upregulation) in the expression of ergosterol genes, suggesting that the ergosterol pathway is targeted by this NP. Consistent with this transcriptional response, analysis of the sterol content of tomatidine-treated cells showed not only inhibition of Erg6 (C-24 sterol methyltransferase) activity but also of Erg4 (C-24 sterol reductase) activity. A forward genetic approach in Saccharomyces cerevisiae coupled with whole-genome sequencing identified 2 nonsynonymous mutations in ERG6 (amino acids D249G and G132D) responsible for tomatidine resistance. Our results therefore unambiguously identified Erg6, a C-24 sterol methyltransferase absent in mammals, to be the main direct target of tomatidine. We tested the in vivo efficacy of tomatidine in a mouse model of C. albicans systemic infection. Treatment with a nanocrystal pharmacological formulation successfully decreased the fungal burden in infected kidneys compared to the fungal burden achieved by the use of placebo and thus confirmed the potential of tomatidine as a therapeutic agent.
Assuntos
Antifúngicos/farmacologia , Produtos Biológicos/farmacologia , Candida albicans/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Candidíase/tratamento farmacológico , Candidíase/microbiologia , Linhagem Celular Tumoral , Farmacorresistência Fúngica/efeitos dos fármacos , Farmacorresistência Fúngica/genética , Ergosterol/farmacologia , Feminino , Fluconazol/farmacologia , Genes Fúngicos/genética , Células HeLa , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana/métodos , Saccharomyces cerevisiae/genética , Tomatina/análogos & derivados , Tomatina/farmacologiaRESUMO
The present study investigated the inhibitory effects of the commercial tetrasaccharide tomato glycoalkaloid tomatine and the aglycone tomatidine on three mucosal pathogenic protozoa that are reported to infect humans, cattle, and cats, respectively: Trichomonas vaginalis strain G3, Tritrichomonas foetus strain D1, and Tritrichomonas foetus strain C1. A preliminary screen showed that tomatine at 100 µM concentration completely inhibited the growth of all three trichomonads. In contrast, the inhibition of all three pathogens by tomatidine was much lower, suggesting the involvement of the lycotetraose carbohydrate side chain in the mechanism of inhibition. Midpoints of concentration-response sigmoid plots of tomatine on the three strains correspond to IC50 values, the concentration that inhibits 50% of growth of the pathogenic protozoa. The concentration data were used to calculate the IC50 values for G3, D1, and C1 of 7.9, 1.9, and 2.2 µM, respectively. The results show an approximately 4-fold variation from the lowest to the highest value (lowest activity). Although the inhibition by tomatine was not as effective as that of the medicinal drug metronidazole, the relatively low IC50 values for both T. vaginalis and T. foetus indicated tomatine as a possible natural alternative therapeutic for trichomoniasis in humans and food-producing (cattle and pigs) and domestic (cats) animals. Because tomatine has the potential to serve as a new antiprotozoan functional (medical) food, the distribution of this glycoalkaloid in tomatoes and suggestions for further research are discussed.
Assuntos
Antiprotozoários/farmacologia , Extratos Vegetais/farmacologia , Solanum lycopersicum/química , Tomatina/análogos & derivados , Tomatina/farmacologia , Trichomonadida/efeitos dos fármacos , Animais , Antiprotozoários/química , Extratos Vegetais/química , Tomatina/química , Trichomonadida/químicaRESUMO
Saponins are used in medicine due to their pharmacological and immunological effects. To better understand interactions of saponins with model membranes and natural membranes of, for example, erythrocytes, Langmuir film balance experiments are well established. For most saponins, a strong interaction with cholesterol was demonstrated in dependence of both the aglycone part and the sugar moieties and is suggested to be correlated with a strong hemolytic activity, high toxicity, and high surface activity, as was demonstrated for the steroid saponin digitonin. In general, changes in the sugar chain or in substituents of the aglycone result in a modification of the saponin properties. A promising saponin with regard to fairly low hemolytic activity and high adjuvant effect is α-tomatine, which still shows a high affinity for cholesterol. An interaction with cholesterol and lipids has also been proven for the Quillaja saponin from the bark of Quillaja saponaria Molina. This triterpene saponin was approved in marketed vaccines as an adjuvant due to the formation of immunostimulating complexes. Immunostimulating complexes consist of a Quillaja saponin, cholesterol, phospholipids, and a corresponding antigen. Recently, another saponin from Quillaja brasiliensis was successfully tested in immunostimulating complexes, too. Based on the results of interaction studies, the formation of drug delivery systems such as immunostimulating complexes or similar self-assembled colloids is postulated for a variety of saponins.
Assuntos
ISCOMs/química , Saponinas/farmacologia , Tomatina/análogos & derivados , Animais , Células Cultivadas , Hemólise , Membranas Artificiais , Camundongos , Modelos Biológicos , Quillaja/química , Saponinas/química , Tomatina/química , Tomatina/isolamento & purificação , Tomatina/farmacologia , Triterpenos/química , Triterpenos/farmacologiaRESUMO
Plants produce a variety of secondary metabolites to defend themselves from pathogen attack, while pathogens have evolved to overcome plant defences by producing enzymes that degrade or modify these defence compounds. However, many compounds targeted by pathogen enzymes currently remain enigmatic. Identifying host compounds targeted by pathogen enzymes would enable us to understand the potential importance of such compounds in plant defence and modify them to make them insensitive to pathogen enzymes. Here, a proof of concept metabolomics-based method was developed to discover plant defence compounds modified by pathogens using two pathogen enzymes with known targets in wheat and tomato. Plant extracts treated with purified pathogen enzymes were subjected to LC-MS, and the relative abundance of metabolites before and after treatment were comparatively analysed. Using two enzymes from different pathogens the in planta targets could be found by combining relatively simple enzymology with the power of untargeted metabolomics. Key to the method is dataset simplification based on natural isotope occurrence and statistical filtering, which can be scripted. The method presented here will aid in our understanding of plant-pathogen interactions and may lead to the development of new plant protection strategies.
Assuntos
Enzimas/metabolismo , Proteínas Fúngicas/metabolismo , Metabolômica/métodos , Compostos Fitoquímicos/metabolismo , Solanum lycopersicum/imunologia , Solanum lycopersicum/microbiologia , Triticum/imunologia , Triticum/microbiologia , Espectrometria de Massas , Compostos Fitoquímicos/química , Tomatina/análogos & derivados , Tomatina/química , Tomatina/metabolismoRESUMO
Glycoalkaloids are secondary metabolites commonly found in Solanaceae plants. They have anti-bacterial, anti-fungal and insecticidal activities. In the present study we examine the effects of potato and tomato leaf extracts and their main components, the glycoalkaloids α-solanine, α-chaconine and α-tomatine, on development and reproduction of Drosophila melanogaster wild-type flies at different stages. Parental generation was exposed to five different concentrations of tested substances. The effects were examined also on the next, non-exposed generation. In the first (exposed) generation, addition of each extract reduced the number of organisms reaching the pupal and imaginal stages. Parent insects exposed to extracts and metabolites individually applied showed faster development. However, the effect was weaker in case of single metabolites than in case of exposure to extracts. An increase of developmental rate was also observed in the next, non-exposed generation. The imagoes of both generations exposed to extracts and pure metabolites showed some anomalies in body size and malformations, such as deformed wings and abdomens, smaller black abdominal zone. Our results further support the current idea that Solanaceae can be an impressive source of molecules, which could efficaciously be used in crop protection, as natural extract or in formulation of single pure metabolites in sustainable agriculture.
Assuntos
Drosophila melanogaster/fisiologia , Extratos Vegetais/farmacologia , Reprodução/efeitos dos fármacos , Solanum lycopersicum/química , Solanum tuberosum/química , Animais , Tamanho Corporal/efeitos dos fármacos , Drosophila melanogaster/efeitos dos fármacos , Drosophila melanogaster/crescimento & desenvolvimento , Feminino , Masculino , Controle Biológico de Vetores , Extratos Vegetais/química , Folhas de Planta/química , Solanina/análogos & derivados , Solanina/farmacologia , Tomatina/análogos & derivados , Tomatina/farmacologiaRESUMO
Steroidal alkaloids are a class of secondary metabolites isolated from plants, amphibians, and marine invertebrates. Evidence accumulated in the recent two decades demonstrates that steroidal alkaloids have a wide range of bioactivities including anticancer, antimicrobial, anti-inflammatory, antinociceptive, etc., suggesting their great potential for application. It is therefore necessary to comprehensively summarize the bioactivities, especially anticancer activities and mechanisms of steroidal alkaloids. Here we systematically highlight the anticancer profiles both in vitro and in vivo of steroidal alkaloids such as dendrogenin, solanidine, solasodine, tomatidine, cyclopamine, and their derivatives. Furthermore, other bioactivities of steroidal alkaloids are also discussed. The integrated molecular mechanisms in this review can increase our understanding on the utilization of steroidal alkaloids and contribute to the development of new drug candidates. Although the therapeutic potentials of steroidal alkaloids look promising in the preclinical and clinical studies, further pharmacokinetic and clinical studies are mandated to define their efficacy and safety in cancer and other diseases.
Assuntos
Alcaloides/uso terapêutico , Neoplasias/tratamento farmacológico , Esteroides/uso terapêutico , Alcaloides/química , Androgênios/química , Animais , Anti-Inflamatórios/química , Antineoplásicos/química , Linhagem Celular Tumoral , Diosgenina/química , Estrogênios/química , Humanos , Camundongos , Alcaloides de Solanáceas/química , Tomatina/análogos & derivados , Tomatina/química , Alcaloides de Veratrum/químicaRESUMO
Tomatoes, members of the Solanaceae plant family, produce biologically active secondary metabolites, including glycoalkaloids, which may have both adverse and beneficial biological effects. Using the linear ion trap (LIT) mass spectrometry, multi-stage collision induced dissociation (CID) experiments (MSn) were performed to elucidate characteristic fragmentation pathways of the glycoalkaloid, tomatidine and of ß1-hydroxytomatine. High resolution with high accuracy mass analysis using an Orbitrap fourier transform MS with higher-energy collisional induced dissociation (HCD) was used to produce mass spectra data across a wide spectral range for confirmation of proposed ion structures and formulae.
Assuntos
Espectrometria de Massas/métodos , Tomatina/análogos & derivados , Estrutura Molecular , Tomatina/químicaRESUMO
Inhibition of cancer can occur via apoptosis, a genetically directed process of cell self-destruction that involves numerous biomarkers and signaling pathways. Glycoalkaloids are nitrogen-containing secondary plant metabolites found in numerous Solanaceous plants including eggplants, potatoes, and tomatoes. Exposure of cancer cells to glycoalkaloids produced by eggplants (α-solamargine and α-solasonine), potatoes (α-chaconine and α-solanine), and tomatoes (α-tomatine) or their hydrolysis products (mono-, di-, and trisaccharide derivatives and the aglycones solasodine, solanidine, and tomatidine) inhibits the growth of the cells in culture (in vitro) as well as tumor growth in vivo. This overview comprehensively surveys and consolidates worldwide efforts to define the following aspects of these natural compounds: (a) their prevalence in the three foods; (b) their chemistry and structure-activity relationships; (c) the reported factors (biomarkers, signaling pathways) associated with apoptosis of bone, breast, cervical, colon, gastric, glioblastoma, leukemia, liver, lung, lymphoma, melanoma, pancreas, prostate, and squamous cell carcinoma cell lines in vitro and the in vivo inhibition of tumor formation and growth in fish and mice and in human skin cancers; and (d) future research needs. The described results may make it possible to better relate the structures of the active compounds to their health-promoting function, individually, in combination, and in food, and allow the consumer to select glycoalkaloid-containing food with the optimal content of nontoxic beneficial compounds. The described findings are expected to be a valuable record and resource for further investigation of the health benefits of food-related natural compounds.
Assuntos
Anticarcinógenos , Alcaloides de Solanáceas/química , Alcaloides de Solanáceas/farmacologia , Solanum lycopersicum/metabolismo , Solanum melongena/metabolismo , Solanum tuberosum/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Camundongos , Alcaloides de Solanáceas/biossíntese , Solanina/análogos & derivados , Solanina/farmacologia , Relação Estrutura-Atividade , Tomatina/análogos & derivados , Tomatina/farmacologiaRESUMO
Several evidences suggest that enhanced oxidative stress is involved in the pathogenesis and/or progression of several neurodegenerative diseases. The aim of this study was to investigate for the first time whether both extracts from tomato plant (Lycopersicon esculentum Mill.) leaves and their isolated steroidal alkaloids (tomatine and tomatidine) afford neuroprotective effect against glutamate-induced toxicity in SH-SY5Y neuroblastoma cells and to elucidate the mechanisms underlying this protection. Steroidal alkaloids from tomato are well known for their cholinesterases' inhibitory capacity and the results showed that both purified extracts and isolated compounds, at non-toxic concentrations for gastric (AGS), intestinal (Caco-2) and neuronal (SH-SY5Y) cells, have the capacity to preserve mitochondria membrane potential and to decrease reactive oxygen species levels of SH-SY5Y glutamate-insulted cells. Moreover, the use of specific antagonists of cholinergic receptors allowed observing that tomatine and tomatidine can interact with nicotinic receptors, specifically with the α7 type. No effect on muscarinic receptors was noticed. In addition to the selective cholinesterases' inhibition revealed by the compounds/extracts, these results provide novel and important insights into their neuroprotective mechanism. This work also demystifies the applicability of these compounds in therapeutics, by demonstrating that their toxicity was overestimated for long time.
Assuntos
Ácido Glutâmico/toxicidade , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Tomatina/análogos & derivados , Tomatina/farmacologia , Células CACO-2 , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/farmacologia , Humanos , Neuroblastoma , Extratos Vegetais/farmacologia , Folhas de Planta/químicaRESUMO
Alpha (α)-tomatine, a major saponin found in tomato has been shown to inhibit the growth of androgen-independent prostate cancer PC-3 cells. The effects of α-tomatine in combination with the chemotherapeutic agent paclitaxel against PC-3 cells were investigated in the present study. Combined treatment with a sub-toxic dose of α-tomatine and paclitaxel significantly decreased cell viability with concomitant increase in the percentage of apoptotic PC-3 cells. The combined treatment, however, had no cytotoxic effect on the non-neoplastic prostate RWPE-1 cells. Apoptosis of PC-3 cells was accompanied by the inhibition of PI3K/Akt pro-survival signaling, an increase in the expression of the pro-apoptotic protein BAD but a decrease in the expressions of anti-apoptotic proteins, Bcl-2 and Bcl-xL. Results from a mouse xenograft model showed the combined treatment completely suppressed subcutaneous tumor growth without significant side effects. Consistent with its in vitro anti-cancer effects, tumor materials from mice showed increased apoptosis of tumor cells with reduced protein expression of activated PI3K/Akt. These results suggest that the synergistic anti-cancer effects of paclitaxel and α-tomatine may be beneficial for refractory prostate cancer treatment.
Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Apoptose/efeitos dos fármacos , Paclitaxel/uso terapêutico , Fitoterapia , Neoplasias da Próstata/tratamento farmacológico , Solanum lycopersicum/química , Tomatina/análogos & derivados , Androgênios/metabolismo , Animais , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Sinergismo Farmacológico , Quimioterapia Combinada , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Paclitaxel/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Próstata/efeitos dos fármacos , Neoplasias da Próstata/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais , Tomatina/farmacologia , Tomatina/uso terapêutico , Proteína X Associada a bcl-2/metabolismo , Proteína de Morte Celular Associada a bcl/metabolismoRESUMO
Partial acid hydrolysis of the tetrasaccharide (lycotetraose) side chain of the tomato glycoalkaloid α-tomatine resulted in the formation of four products with three, two, one, and zero carbohydrate side chains, which were separated by high-performance liquid chromatography (HPLC) and identified by thin-layer chromatography (TLC) and liquid chromatography ion-trap time-of-flight mass spectrometry (LCMS-IT-TOF). The inhibitory activities in terms of IC(50) values (concentration that inhibits 50% of the cells under the test conditions) of the parent compound and the hydrolysates, isolated by preparative HPLC, against normal human liver and lung cells and human breast, gastric, and prostate cancer cells indicate that (a) the removal of sugars significantly reduced the concentration-dependent cell-inhibiting effects of the test compounds, (b) PC3 prostate cancer cells were about 10 times more susceptible to inhibition by α-tomatine than the breast and gastric cancer cells or the normal cells, (c) the activity of α-tomatine against the prostate cancer cells was 200 times greater than that of the aglycone tomatidine, and (d) the activity increased as the number of sugars on the aglycone increased, but this was only statistically significant at p < 0.05 for the normal lung Hel299 cell line. The effect of the alkaloids on tumor necrosis factor α (TNF-α) was measured in RAW264.7 macrophage cells. There was a statistically significant negative correlation between the dosage of γ- and α-tomatine and the level of TNF-α. α-Tomatine was the most effective compound at reducing TNF-α. The dietary significance of the results and future research needs are discussed.
Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Tomatina/química , Tomatina/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/fisiopatologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Solanum lycopersicum/química , Masculino , Estrutura Molecular , Próstata , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/fisiopatologia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/fisiopatologia , Tomatina/análogos & derivadosRESUMO
It was previously revealed that esculeoside A, a new glycoalkaloid, and esculeogenin A, a new aglycon of esculeoside A, contained in ripe tomato ameliorate atherosclerosis in apoE-deficent mice. This study examined whether tomatidine, the aglycone of tomatine, which is a major tomato glycoalkaloid, also shows similar inhibitory effects on cholesterol ester (CE) accumulation in human monocyte-derived macrophages (HMDM) and atherogenesis in apoE-deficient mice. Tomatidine significantly inhibited the CE accumulation induced by acetylated LDL in HMDM in a dose-dependent manner. Tomatidine also inhibited CE formation in Chinese hamster ovary cells overexpressing acyl-CoA:cholesterol acyl-transferase (ACAT)-1 or ACAT-2, suggesting that tomatidine suppresses both ACAT-1 and ACAT-2 activities. Furthermore, the oral administration of tomatidine to apoE-deficient mice significantly reduced levels of serum cholesterol, LDL-cholesterol, and areas of atherosclerotic lesions. The study provides the first evidence that tomatidine significantly suppresses the activity of ACAT and leads to reduction of atherogenesis.