RESUMO
Colon cancer remains a clinical challenge in industrialised countries. Its treatment with 5-Flurouracil (5-FU) develops many side effects and resistance. Thus, several strategies have been undertaken so far, including the use of drug cocktails and polypharmacology. Heme oxygenase-1 (HO-1) is an emerging molecular target in the treatment of various cancers. We recently demonstrated that a combination of HO-1 inhibitors with 5-FU and the corresponding hybrids SI1/17, SI1/20, and SI1/22, possessed anticancer activity against prostate and lung cancer cells. In this work, we evaluated these hybrids in a model of colon cancer and found that SI1/22 and the respective combo have greater potency than 5-FU. Particularly, compounds inhibit HO-1 activity in cell lysates, increase ROS and the expression of HO-1, SOD, and Nrf2. Moreover, we observed a decrease of pro-caspase and an increase in cleaved PARP-1 and p62, suggesting apoptotic and autophagic cell death and potential application of these drugs as anticancer agents.
Assuntos
Antineoplásicos , Neoplasias do Colo , Fluoruracila , Humanos , Masculino , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Fluoruracila/farmacologia , Heme Oxigenase-1/antagonistas & inibidoresRESUMO
The overexpression of σ receptors (σRs) in various types of tumors has prompted a deep investigation of their role in cancer pathophysiology. Consequently, σR ligands have been widely studied in vitro and in vivo for their antiproliferative effects as a novel potential class of chemotherapeutic agents, both alone and in combination with other anticancer drugs. A growing body of evidence highlights that σR ligands can inhibit cancer cells' survival, migration, and proliferation, thanks to the modulation of a wide panel of tumorigenic pathways. In addition to their antitumor activity, σR ligands are gaining momentum as radiotracers for PET and SPECT imaging applications. The purpose of this review is to report on recent advances in the development of σR ligands. In particular, herein, we describe the structure-activity relationships of structurally diverse mixed σ1R/σ2R ligands that showed promising antitumor profiles towards a variety of cancer cell lines.
Assuntos
Antineoplásicos , Neoplasias , Receptores sigma , Antineoplásicos/farmacologia , Humanos , Ligantes , Receptores sigma/metabolismo , Relação Estrutura-AtividadeRESUMO
The term ferroptosis refers to a peculiar type of programmed cell death (PCD) mainly characterized by extensive iron-dependent lipid peroxidation. Recently, ferroptosis has been suggested as a potential new strategy for the treatment of several cancers, including breast cancer (BC). In particular, among the BC subtypes, triple negative breast cancer (TNBC) is considered the most aggressive, and conventional drugs fail to provide long-term efficacy. In this context, our study's purpose was to investigate the mechanism of ferroptosis in breast cancer cell lines and reveal the significance of heme oxygenase (HO) modulation in the process, providing new biochemical approaches. HO's effect on BC was evaluated by MTT tests, gene silencing, Western blot analysis, and measurement of reactive oxygen species (ROS), glutathione (GSH) and lipid hydroperoxide (LOOH) levels. In order to assess HO's implication, different approaches were exploited, using two distinct HO-1 inducers (hemin and curcumin), a well-known HO inhibitor (SnMP) and a selective HO-2 inhibitor. The data obtained showed HO's contribution to the onset of ferroptosis; in particular, HO-1 induction seemed to accelerate the process. Moreover, our results suggest a potential role of HO-2 in erastin-induced ferroptosis. In view of the above, HO modulation in ferroptosis can offer a novel approach for breast cancer treatment.
Assuntos
Ferroptose , Heme Oxigenase (Desciclizante) , Neoplasias de Mama Triplo Negativas , Glutationa , Heme Oxigenase (Desciclizante)/metabolismo , Humanos , Peróxidos Lipídicos , Espécies Reativas de Oxigênio/metabolismoRESUMO
This paper reports on a novel series of tyrosine kinase inhibitors (TKIs) potentially useful for the treatment of chronic myeloid leukemia (CML). The newly designed and synthesized compounds are structurally related to nilotinib (NIL), a second-generation oral TKI, and to a series of imatinib (IM)-based TKIs, previously reported by our research group, these latter characterized by a hybrid structure between TKIs and heme oxygenase-1 (HO-1) inhibitors. The enzyme HO-1 was selected as an additional target since it is overexpressed in many cases of drug resistance, including CML. The new derivatives 1a-j correctly tackle the chimeric protein BCR-ABL. Therefore, the inhibition of TK was comparable to or higher than NIL and IM for many novel compounds, while most of the new analogs showed only moderate potency against HO-1. Molecular docking studies revealed insights into the binding mode with BCR-ABL and HO-1, providing a structural explanation for the differential activity. Cytotoxicity on K562 CML cells, both NIL-sensitive and -resistant, was evaluated. Notably, some new compounds strongly reduced the viability of K562 sensitive cells.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Inibidores de Proteínas Quinases , Doença Crônica , Humanos , Mesilato de Imatinib/farmacologia , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
Leishmaniasis is an infectious disease caused by parasites of the genus Leishmania and transmitted by the bite of a sand fly. To date, most available drugs for treatment are toxic and beyond the economic means of those affected by the disease. Protein disulfide isomerase (PDI) is a chaperone protein that plays a major role in the folding of newly synthesized proteins, specifically assisting in disulfide bond formation, breakage, or rearrangement in all non-native proteins. In previous work, we demonstrated that Leishmania major PDI (LmPDI) has an essential role in pathogen virulence. Furthermore, inhibition of LmPDI further blocked parasite infection in macrophages. In this study, we utilized a computer-aided approach to design a series of LmPDI inhibitors. Fragment-based virtual screening allowed for the understanding of the inhibitors' modes of action on LmPDI active sites. The generated compounds obtained after multiple rounds of virtual screening were synthesized and significantly inhibited target LmPDI reductase activity and were shown to decrease in vitro parasite growth in human monocyte-derived macrophages. This novel cheminformatics and synthetic approach led to the identification of a new series of compounds that might be optimized into novel drugs, likely more specific and less toxic for the treatment of leishmaniasis.
Assuntos
Anti-Infecciosos/síntese química , Inibidores Enzimáticos/química , Hexaclorofeno/síntese química , Leishmania major/enzimologia , Leishmaniose/tratamento farmacológico , Isomerases de Dissulfetos de Proteínas/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/síntese química , Anti-Infecciosos/farmacologia , Domínio Catalítico , Desenho Assistido por Computador , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Hexaclorofeno/farmacologia , Humanos , Simulação de Acoplamento Molecular , Ligação Proteica , Conformação Proteica , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-AtividadeRESUMO
Up-regulation of HO-1 had been frequently reported in different cases and types of human malignancies. Since poor clinical outcomes are reported in these cases, this enzyme's inhibition is considered a valuable and proven anticancer approach. To identify novel HO-1 inhibitors suitable for drug development, we report a structure-guided fragment-based approach to identify new lead compounds. Different parts of the selected molecules were analyzed, and the different series of novel compounds were virtually evaluated. The growing experiments of the classical HO-1 inhibitors structure led us to different hit-compounds. A synthetic pathway for six selected molecules was designed, and the compounds were synthesized. The biological activity revealed that molecules 10 and 12 inhibit the HO-1 activity with an IC50 of 1.01 and 0.90 µM, respectively. This study suggested that our growing approach was successful, and these results are ongoing for further development.
Assuntos
Inibidores Enzimáticos/farmacologia , Heme Oxigenase (Desciclizante)/antagonistas & inibidores , Imidazóis/farmacologia , Animais , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Heme Oxigenase (Desciclizante)/metabolismo , Imidazóis/síntese química , Imidazóis/química , Ligantes , Modelos Moleculares , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
In this work, the first mutual prodrug of 5-fluorouracil and heme oxygenase1 inhibitor (5-FU/HO-1 hybrid) has been designed, synthesised, and evaluated for its in vitro chemical and enzymatic hydrolysis stability. Predicted in silico physicochemical properties of the newly synthesised hybrid (3) demonstrated a drug-like profile with suitable Absorption, Distribution, Metabolism, and Excretion (ADME) properties and low toxic liabilities. Preliminary cytotoxicity evaluation towards human prostate (DU145) and lung (A549) cancer cell lines demonstrated that 3 exerted a similar effect on cell viability to that produced by the reference drug 5-FU. Among the two tested cancer cell lines, the A549 cells were more susceptible for 3. Of note, hybrid 3 also had a significantly lower cytotoxic effect on healthy human lung epithelial cells (BEAS-2B) than 5-FU. Altogether our results served as an initial proof-of-concept to develop 5-FU/HO-1 mutual prodrugs as potential novel anticancer agents.
Assuntos
Antineoplásicos/farmacologia , Fluoruracila/química , Heme Oxigenase-1/química , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Pró-Fármacos/síntese química , Ratos , Ratos Sprague-Dawley , SuínosRESUMO
Cancer is a multifactorial disease that may be tackled by targeting different signaling pathways. Heme oxygenase-1 (HO-1) and sigma receptors (σRs) are both overexpressed in different human cancers, including prostate and brain, contributing to the cancer spreading. In the present study, we investigated whether HO-1 inhibitors and σR ligands, as well a combination of the two, may influence DU145 human prostate and U87MG human glioblastoma cancer cells proliferation. In addition, we synthesized, characterized, and tested a small series of novel hybrid compounds (HO-1/σRs) 1-4 containing the chemical features needed for HO-1 inhibition and σR modulation. Herein, we report for the first time that targeting simultaneously HO-1 and σR proteins may be a good strategy to achieve increased antiproliferative activity against DU145 and U87MG cells, with respect to the mono administration of the parent compounds. The obtained outcomes provide an initial proof of concept useful to further optimize the structure of HO-1/σRs hybrids to develop novel potential anticancer agents.
Assuntos
Antineoplásicos , Inibidores Enzimáticos , Heme Oxigenase-1/antagonistas & inibidores , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias , Receptores sigma/antagonistas & inibidores , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Heme Oxigenase-1/metabolismo , Humanos , Proteínas de Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Ratos , Receptores sigma/metabolismoRESUMO
Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related death mainly due to its high metastatic rate. Impairment of redox homeostasis mechanisms has been previously described in NSCLC and is associated with the disease itself as well as with comorbidities such as smoking. The aim of the present in vitro study was to evaluate the effect of selective and non-competitive inhibition of heme oxygenase-1 (HO-1) on cancer redox homeostasis with particular regards to glutathione (GSH) metabolism related enzymes. NSCLC cell line (A549) was treated with the HO-1 activity inhibitor VP13/47 (10 µM) and we further evaluated cell viability, apoptosis, mitochondrial dysfunction and oxidative stress. Our results showed that VP13/47 significantly reduced HO-1 expression and total HO activity thus, resulting in a significant reduction of cell viability, proliferation and increased apoptosis, mitochondrial dysfunction and oxidative stress. Consistently with increased oxidative stress, we also showed that reduced GSH was significantly decreased and such effect was also accompanied by a significant downregulation of the enzymes involved in its biosynthesis. Taken all together our results show that selective HO-1 inhibition significantly impairs NSCLC progression and may represent a possible pharmacological strategy for new chemotherapy agents.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Inibidores Enzimáticos/farmacologia , Glutationa/metabolismo , Heme Oxigenase-1/antagonistas & inibidores , Hidrocarbonetos Bromados/farmacologia , Imidazóis/farmacologia , Neoplasias Pulmonares/metabolismo , Células A549 , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo , Inibidores Enzimáticos/química , Humanos , Hidrocarbonetos Bromados/química , Imidazóis/química , Neoplasias Pulmonares/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Estresse OxidativoRESUMO
The enzymatic family of heme oxygenase (HO) is accountable for heme breakdown. Among the two isoforms characterized to date, HO-2 is poorly investigated due to the lack of potent HO-2 chemical modulators and the greater attentiveness towards HO-1 isoform. In the present paper, we report the rational design and synthesis of HO-2 inhibitors achieved by modulating the volume of known HO-1 inhibitors. The inhibition preference has been moved from HO-1 to HO-2 by merely increasing the volume of the substituent in the western region of the inhibitors. Docking studies demonstrated that new derivatives soak differently in the two binding pockets, probably due to the presence of a Tyr187 residue in HO-2. These findings could be useful for the design of new selective HO-2 compounds.
Assuntos
Inibidores Enzimáticos/farmacologia , Heme Oxigenase (Desciclizante)/antagonistas & inibidores , Nitrilas/farmacologia , Algoritmos , Animais , Encéfalo/enzimologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Heme Oxigenase (Desciclizante)/metabolismo , Interações Hidrofóbicas e Hidrofílicas , Simulação de Acoplamento Molecular , Estrutura Molecular , Nitrilas/síntese química , Nitrilas/química , Ratos , Baço/enzimologia , Relação Estrutura-AtividadeRESUMO
Heme oxygenase-1 (HO-1) has been recognized as extensively involved in the development and aggravation of cancer, cell propagation and at in the mechanism of chemoresistance development. Low micromolar HO-1 inhibitors selective towards HO-2 has been recently reported, wherein the azole core and the hydrophobic residues are linked through a phenylethanolic spacer bearing a chiral center. Since less information are known about the stereoselective requirements for HO-1 inhibition, here we report the enantiomeric resolution of 1-(biphenyl-3-yl)-2-(1H-imidazol-1-yl)ethanol (1) and 1-[4-[(4-bromobenzyl)oxy]phenyl]-2-(1H-imidazol-1-yl)ethanol (2), two among the most potent and selective HO-1 inhibitors known thus far when tested as racemates. The absolute configuration was established for 1 by a combination of experimental and in silico derived electronic circular dichroism spectra, while docking approaches were useful in the case of compound 2. Biological evaluation of pure enantiomers highlighted higher HO-1 inhibitory activity of (R)-enantiomers. Docking studies demonstrated the importance of hydrogen bond interaction, more pronounced for the (R)-enantiomers, with a consensus water molecule within the binding pocket. The present study demonstrates that differences in three-dimensional structure amongst compounds 1 and 2 enantiomers affect significantly the selectivity of these HO-1 inhibitors.
Assuntos
Azóis/farmacologia , Inibidores Enzimáticos/farmacologia , Álcool Feniletílico/farmacologia , Animais , Azóis/química , Teoria da Densidade Funcional , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Heme Oxigenase (Desciclizante)/antagonistas & inibidores , Heme Oxigenase (Desciclizante)/metabolismo , Masculino , Simulação de Acoplamento Molecular , Estrutura Molecular , Álcool Feniletílico/química , Ratos , Ratos Sprague-Dawley , Baço/enzimologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Novel heme oxygenase-1 (HO-1) inducers based on dimethyl fumarate (DMF) structure are reported in this paper. These compounds are obtained by modification of the DMF backbone. Particularly, maintaining the α, ß-unsaturated dicarbonyl function as the central chain crucial for HO-1 induction, different substituted or unsubstituted phenyl rings are introduced by means of an ester or amide linkage. Symmetric and asymmetric derivatives are synthesized. All compounds are tested on a human hepatic stellate cell line LX-2 to assay their capacity for modifying HO-1 expression. Compounds 1b, 1l and 1m stand out for their potency as HO-1 inducers, being 2-3 fold more active than DMF, and for their ability to reverse reactive oxygen species (ROS) production mediated using palmitic acid (PA). These properties, coupled with a low toxicity toward LX-2 cell lines, make these compounds potentially useful for treatment of diseases in which HO-1 overexpression may counteract inflammation, such as hepatic fibrosis. Docking studies show a correlation between predicted binding free energy and experimental HO-1 expression data. These preliminary results may support the development of new approaches in the management of liver fibrosis.
Assuntos
Fumarato de Dimetilo/química , Fumarato de Dimetilo/farmacologia , Heme Oxigenase-1/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Linhagem Celular , Fumarato de Dimetilo/análogos & derivados , Fumarato de Dimetilo/síntese química , Humanos , Simulação de Acoplamento Molecular , Ácido Palmítico/farmacologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
In this paper, a novel series of imidazole-based heme oxygenase-1 (HO-1) inhibitors is reported. These compounds were obtained by modifications of previously described high potent and selective arylethanolimidazoles. In particular, simplification of the central linker and repositioning of the hydrophobic portion were carried out. Results indicate that a hydroxyl group in the central region is crucial for the potency as well as the spatial distribution of the hydrophobic portion. Docking studies revealed a similar interaction of the classical HO-1 inhibitors with the active site of the protein. The most potent and selective compound (5a) was tested for its potential cytotoxic activity against hormone-sensitive and hormone-resistant breast cancer cell lines (MCF-7 and MDA-MB-231).
Assuntos
Antineoplásicos/síntese química , Neoplasias da Mama/enzimologia , Heme Oxigenase-1/antagonistas & inibidores , Imidazóis/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imidazóis/química , Imidazóis/farmacologia , Células MCF-7 , Simulação de Acoplamento Molecular , Estrutura MolecularRESUMO
The synthesis of seventeen new 1,3-diaryl-5-oxo-proline derivatives as endothelin receptor (ETR) ligands is described. The structural configuration of the new molecules was determined by analyzing selected signals in proton NMR spectra. In vitro binding assays of the human ETA and ETB receptors allowed us to identify compound 31h as a selective ETAR ligand. The molecular docking of the selected compounds and the ETA antagonist atrasentan in the ETAR homology model provided insight into the structural elements required for the affinity and the selectivity of the ETAR subtype.
Assuntos
Técnicas de Química Sintética , Dipeptídeos/química , Modelos Moleculares , Receptor de Endotelina A/química , Sítios de Ligação , Dipeptídeos/síntese química , Ligantes , Conformação Molecular , Estrutura Molecular , Ligação Proteica , Receptor de Endotelina A/metabolismo , Análise EspectralRESUMO
Crocin and crocetin are two interesting constituents of saffron (Crocus sativus) that possess important biological activities. Their use as therapeutic agents is strongly compromised by a scarce stability, poor absorption, and low bioavailability. Therefore, to improve these unfavorable features, the aim of the present work has been to apply a nanotechnological approach based on the formulation of solid lipid nanoparticles containing crocin and crocetin. Solid lipid nanoparticles were formulated according to crocin and crocetin chemical properties, using a variation of the quasi-emulsion solvent diffusion method to formulate crocin-solid lipid nanoparticles, while crocetin-solid lipid nanoparticles were prepared following the solvent diffusion method. Morphology and dimensional distribution of solid lipid nanoparticles have been characterized by differential scanning calorimetry and photon correlation spectroscopy, respectively, while the effect of drug incorporation versus time has been studied by Turbiscan technology. In order to verify the role of the nanotechnological approach on the biological activities of crocin and crocetin, the antioxidant and antiproliferative effects of these carotenoids once incorporated in lipid nanoparticles have been evaluated. For this aim, the oxygen radical absorbance capacity assay and the MTT test were used, respectively.The results pointed out the formulation of nanometric dispersions endowed with high homogeneity and stability, with an encapsulation efficiency ranging from 80 (crocetin-solid lipid nanoparticles) to 94% (crocin-crocetin). The oxygen radical absorbance capacity assay evidenced an interesting and prolonged antioxidant activity of crocin and crocetin once encapsulated in solid lipid nanoparticles, while the nanoencapsulation strategy showed a different mechanism in ameliorating the cytotoxic effect of these two substances.
Assuntos
Antioxidantes/administração & dosagem , Carotenoides/administração & dosagem , Citotoxinas/administração & dosagem , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Antioxidantes/farmacocinética , Disponibilidade Biológica , Carotenoides/farmacocinética , Linhagem Celular Tumoral , Citotoxinas/farmacocinética , Sistemas de Liberação de Medicamentos , Humanos , Nanopartículas , Vitamina A/análogos & derivadosRESUMO
Over-regulation of Heme oxygenase 1 (HO-1) has been recently identified in many types of human cancer, and in these cases, poor clinical outcomes are normally reported. Indeed, the inhibition of HO-1 is being considered as an anticancer approach. Imidazole scaffold is normally present in most of the classical HO-1 inhibitors and seems indispensable to the inhibitory activity due to its strong interaction with the Fe(II) of the heme group. In this paper, we searched for new potentially HO-1 inhibitors among three different databases: Marine Natural Products (MNP), ZINC Natural Products (ZNP) and Super Natural II (SN2). 484,527 compounds were retrieved from the databases and filtered through four statistical/computational filters (2D descriptors, 2D-QSAR pharmacophoric model, 3D-QSAR pharmacophoric model, and docking). Different imidazole-based compounds were suggested by our methodology to be potentially active in inhibiting the HO-1, and the results have been rationalized by the bioactivity of the filtered molecules reported in the literature.
Assuntos
Produtos Biológicos/farmacologia , Inibidores Enzimáticos/farmacologia , Heme Oxigenase-1/antagonistas & inibidores , Imidazóis/farmacologia , Produtos Biológicos/química , Simulação por Computador , Bases de Dados Factuais , Inibidores Enzimáticos/química , Ensaios de Triagem em Larga Escala , Imidazóis/química , Ligantes , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Quantitativa Estrutura-AtividadeRESUMO
High levels of heme oxygenase (HO)-1 have been frequently reported in different human cancers, playing a major role in drug resistance and regulation of cancer cell redox homeostasis. Metformin (MET), a drug widely used for type 2 diabetes, has recently gained interest for treating several cancers. Recent studies indicated that the anti-proliferative effects of metformin in cancer cells are highly dependent on glucose concentration. The present work was directed to determine whether use of a specific inhibitor of HO-1 activity, alone or in combination with metformin, affected metastatic prostate cancer cell viability under different concentrations of glucose. MTT assay and the xCELLigence system were used to evaluate cell viability and cell proliferation in DU145 human prostate cancer cells. Cell apoptosis and reactive oxygen species were analyzed by flow cytometry. The activity of HO-1 was inhibited using a selective imidazole-based inhibitor; genes associated with antioxidant systems and cell death were evaluated by qRT-PCR. Our study demonstrates that metformin suppressed prostate cancer growth in vitro and increased oxidative stress. Disrupting the antioxidant HO-1 activity, especially under low glucose concentration, could be an attractive approach to potentiate metformin antineoplastic effects and could provide a biochemical basis for developing HO-1-targeting drugs against solid tumors.
Assuntos
Apoptose/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Glucose/metabolismo , Heme Oxigenase-1/antagonistas & inibidores , Metformina/farmacologia , Neoplasias da Próstata/metabolismo , Linhagem Celular Tumoral , Heme Oxigenase-1/metabolismo , Humanos , Masculino , Espécies Reativas de Oxigênio/metabolismoRESUMO
Type 1 diabetes mellitus (T1D) is a chronic autoimmune disease resulting in the destruction of insulin producing ß-cells of the pancreas, with consequent insulin deficiency and excessive glucose production. Hyperglycemia results in increased levels of reactive oxygen species (ROS) and nitrogen species (RNS) with consequent oxidative/nitrosative stress and tissue damage. Oxidative damage of the pancreatic tissue may contribute to endothelial dysfunction associated with diabetes. The aim of the present study was to investigate if the potentially protective effects of phenethyl ester of caffeic acid (CAPE), a natural phenolic compound occurring in a variety of plants and derived from honeybee hive propolis, and of a novel CAPE analogue, as heme oxygenase-1 (HO-1) inducers, could reduce pancreatic oxidative damage induced by excessive amount of glucose, affecting the nitric oxide synthase/dimethylarginine dimethylaminohydrolase (NOS/DDAH) pathway in streptozotocin-induced type 1 diabetic rats. Our data demonstrated that inducible nitric oxide synthase/gamma-Glutamyl-cysteine ligase (iNOS/GGCL) and DDAH dysregulation may play a key role in high glucose mediated oxidative stress, whereas HO-1 inducers such as CAPE or its more potent derivatives may be useful in diabetes and other stress-induced pathological conditions.
Assuntos
Antioxidantes/administração & dosagem , Ácidos Cafeicos/administração & dosagem , Diabetes Mellitus Experimental/tratamento farmacológico , Heme Oxigenase (Desciclizante)/metabolismo , Álcool Feniletílico/análogos & derivados , Amidoidrolases/metabolismo , Animais , Antioxidantes/farmacologia , Ácidos Cafeicos/farmacologia , Diabetes Mellitus Experimental/metabolismo , Glutamato-Cisteína Ligase/metabolismo , Masculino , Óxido Nítrico Sintase Tipo II/metabolismo , Álcool Feniletílico/administração & dosagem , Álcool Feniletílico/farmacologia , Própole/química , Ratos , Ratos Wistar , Estreptozocina , Regulação para CimaRESUMO
HO-1 inhibition is considered a valuable anticancer approach. In fact, up-regulation of HO-1 had been repeatedly reported in many types of human malignancies, and in these clinical cases, poor outcomes are reported. To identify novel HO-1 inhibitors suitable for drug development, a scaffold-hopping strategy calculation was utilized to design novel derivatives. Different parts of the selected molecule were analyzed and the different series of novel compounds were virtually evaluated. The calculation for the linker moiety of the classical HO-1 inhibitors structure led us to compounds 5 and 6. A synthetic pathway for the two molecules was designed and the compounds were synthesized. The biological activity revealed an HO-1 inhibition of 0.9 and 54⯵M for molecules 5 and 6 respectively. This study suggested that our scaffold-hopping approach was successful and these results are ongoing for further development.