RESUMO
PURPOSE: To synthesize pegylated stoichiometrically and structurally well-defined conjugates of fullerene (C60) with doxorubicin (DOX) and investigate their antiproliferative effect against cancer cell lines. METHODS: Stoichiometric (1:1 and 1:2) pegylated conjugates of C60 with DOX were synthesized using the Prato reaction to create fulleropyrrolidines equipped with a carboxyl function for anchoring a polyethylene glycol (PEG) moiety and either a hydroxyl group for attaching one molecule of DOX or a terminal alkyne group for attaching two molecules of DOX through a click reaction. In both conjugates, the DOX moieties are held through a urethane-type bond. Drug release was studied in phosphate buffer (PBS, pH 7.4) and MCF-7 cancer cells lysate. The uptake of the conjugates by MCF-7 cancer cells and their intracellular localization were studied with fluorescence microscopy. The antiproliferative activity of the conjugates was investigated using the WST-1 test. RESULTS: One or two DOX molecules were anchored on pegylated C60 particles to form DOX-C60-PEG conjugates. Drug liberation from the conjugates was significantly accelerated in the presence of tumor cell lysate compared to PBS. The conjugates could be internalized by MCF-7 cells. DOX from the conjugates exhibited much delayed, compared to free DOX, localization in the nucleus and antiproliferative activity. CONCLUSION: Pegylated DOX-C60 conjugates (1:1) and (2:1) with well-defined structure were successfully synthesized and found to exhibit comparable, but with a delayed onset, antiproliferative activity with free DOX against MCF-7 cancer cells. The results obtained justify further investigation of the potential of these conjugates as anticancer nanomedicines.
Assuntos
Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacologia , Doxorrubicina/análogos & derivados , Doxorrubicina/farmacologia , Antibióticos Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Feminino , Fulerenos/administração & dosagem , Fulerenos/química , Fulerenos/farmacologia , Humanos , Células MCF-7 , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/química , Polietilenoglicóis/farmacologiaRESUMO
Proteoglycans are major constituents of extracellular matrices, as well as cell surfaces and basement membranes. They play key roles in supporting the dynamic extracellular matrix by generating complex structural networks with other macromolecules and by regulating cellular phenotypes and signaling. It is becoming evident, however, that proteolytic enzymes are required partners for matrix remodeling and for modulating cell signaling via matrix constituents. Proteinases contribute to all stages of diseases, particularly cancer development and progression, and contextually participate in either the removal of damaged products or in the processing of matrix molecules and signaling receptors. The dynamic interplay between proteoglycans and proteolytic enzymes is a crucial biological step that contributes to the pathophysiology of cancer and inflammation. Moreover, proteoglycans are implicated in the expression and secretion of proteolytic enzymes and often modulate their activities. In this review, we describe the emerging biological roles of proteoglycans and proteinases, with a special emphasis on their complex interplay. We critically evaluate this important proteoglycan-proteinase interactome and discuss future challenges with respect to targeting this axis in the treatment of cancer.
Assuntos
Proteínas ADAM/metabolismo , Catepsinas/metabolismo , Metaloproteinases da Matriz/metabolismo , Neoplasias/patologia , Proteoglicanas/metabolismo , Proteínas ADAM/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Glicosaminoglicanos/metabolismo , Humanos , Inibidores de Metaloproteinases de Matriz/farmacologia , Inibidores de Metaloproteinases de Matriz/uso terapêutico , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológicoRESUMO
Novel Carbon Nanotube-Polymer Hybrids were synthesized as potential materials for the development of membranes for water treatment applications in the field of Membrane Bioreactors (MBRs). Due to the toxicological concerns regarding the use of nanomaterials in water treatment as well as the rising demand for safe drinking water to protect public health, we studied the functionalization of MWCNTs and Thin-MWCNTs as to control their properties and increase their ability of embedment into porous anisotropic polymeric membranes. Following the growth of the hydrophilic monomer on the surface of the properly functionalized CNTs, that act as initiator for the controlled radical polymerization (ATRP) of sodium styrene sulfonate (SSNa), the antimicrobial quaternized phosphonium and ammonium salts were attached on CNTs-g-PSSNa through non-covalent bonding. In another approach the covalent attachment of quaternized ammonium polymeric moieties of acrylic acid-vinyl benzyl chloride copolymers with N,N-dimethylhexadecylamine (P(AA12-co-VBCHAM)) on functionalized CNTs has also been attempted. Finally, the toxicological assessment in terms of cell viability and cell morphological changes revealed that surface characteristics play a major role in the biological response of functionalized CNTs.
Assuntos
Nanoestruturas/química , Nanotubos de Carbono/química , Polímeros/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Humanos , Interações Hidrofóbicas e Hidrofílicas , Nanoestruturas/toxicidadeRESUMO
Extensive experimental evidence in cell and animal tumor models show that hyaluronan-CD44 interactions are crucial in both malignancy and resistance to cancer therapy. Because of the intimate relationship between the hyaluronan-CD44 system and tumor cell survival and growth, it is an increasingly investigated area for applications to anticancer chemotherapeutics. Interference with the hyaluronan-CD44 interaction by targeting drugs to CD44, targeting drugs to the hyaluronan matrix, or interfering with hyaluronan matrix/tumor cell-associated CD44 interactions is a viable strategy for cancer treatment. Many of these methods can decrease tumor burden in animal models but have yet to show significant clinical utility. Recent advances in nanomedicine have offered new valuable tools for cancer detection, prevention, and treatment. The enhanced permeability and retention effect has served as key rationale for using nanoparticles to treat solid tumors. However, the targeted and uniform delivery of these particles to all regions of tumors in sufficient quantities requires optimization. An ideal nanocarrier should be equipped with selective ligands that are highly or exclusively expressed on target cells and thus endow the carriers with specific targeting capabilities. In this review, we describe how the hyaluronan-CD44 system may provide such an alternative in tumors expressing specific CD44 variants.
Assuntos
Antineoplásicos/química , Receptores de Hialuronatos/química , Ácido Hialurônico/química , Nanomedicina/métodos , Neoplasias/metabolismo , Animais , Portadores de Fármacos , Terapia Genética/métodos , Humanos , Camundongos , Nanopartículas , Neoplasias/tratamento farmacológico , Ligação Proteica , Transdução de SinaisRESUMO
Extracellular matrix (ECM) components form a dynamic network of key importance for cell function and properties. Key macromolecules in this interplay are syndecans (SDCs), a family of transmembrane heparan sulfate proteoglycans (HSPGs). Specifically, heparan sulfate (HS) chains with their different sulfation pattern have the ability to interact with growth factors and their receptors in tumor microenvironment, promoting the activation of different signaling cascades that regulate tumor cell behavior. The affinity of HS chains with ligands is altered during malignant conditions because of the modification of chain sequence/sulfation pattern. Furthermore, matrix degradation enzymes derived from the tumor itself or the tumor microenvironment, like heparanase and matrix metalloproteinases, ADAM as well as ADAMTS are involved in the cleavage of SDCs ectodomain at the HS and protein core level, respectively. Such released soluble SDCs "shed SDCs" in the ECM interact in an autocrine or paracrine manner with the tumor or/and stromal cells. Shed SDCs, upon binding to several matrix effectors, such as growth factors, chemokines, and cytokines, have the ability to act as competitive inhibitors for membrane proteoglycans, and modulate the inflammatory microenvironment of cancer cells. It is notable that SDCs and their soluble counterparts may affect either the behavior of cancer cells and/or their microenvironment during cancer progression. The importance of these molecules has been highlighted since HSPGs have been proposed as prognostic markers of solid tumors and hematopoietic malignancies. Going a step further down the line, the multi-actions of SDCs in many levels make them appealing as potential pharmacological targets, either by targeting directly the tumor or indirectly the adjacent stroma.
RESUMO
Traditionally, the studies on cancer growth and progression have been focused on the transformed, malignant cells. However, it is now well recognized that the tumour stroma represents a crucial parameter in tumour development, growth and progression. Indeed, several cancers are characterized by a prominent stromal compartment and it is the interactions between cancer cells, stromal cells and extracellular matrix (ECM) components that control the overall tumour growth. Among stromal cells, fibroblasts represent the most important type. They are responsible for deposition and remodeling of ECM components, as well as for the release of cytokines and growth factors, including platelet-derived growth factor (PDGF), acting in a paracrine manner on cancer cells. In this review we elucidate the role of tumor stroma interactions, the roles of PDGF receptor signaling in cancer-associated fibroblasts via alteration of stromal matrix composition and the mitogenic effects of cancer-derived PDGFs. Focus on the targeting of tumor microenvironment at the level of PDGF/PDGF receptor (PDGFR) is also presented as to stimulate further studies for designing and development of novel pharmaceutical agents and combined pharmaceutical interventions. Conclusively, PDGF/PDGFR axis is of paramount importance in the tumour microenvironment context and the inhibition of PDGF receptors' activation represents a major target for future anticancer therapies.
Assuntos
Fibroblastos/metabolismo , Terapia de Alvo Molecular , Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptores do Fator de Crescimento Derivado de Plaquetas/metabolismo , Transdução de Sinais , Microambiente Tumoral/efeitos dos fármacos , Matriz Extracelular/metabolismo , Fibroblastos/efeitos dos fármacos , Humanos , Modelos Biológicos , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: Previous clinical studies advocated that probiotics beneficially affect acute radiation-induced diarrhea. These encouraging results were attributed to the restoration of the intestinal flora; however, there is lack of evidence if and how probiotics influence the underlying pathophysiological mechanisms. AIMS: The present study was conducted to investigate the potential supporting role of a synbiotic preparation (combination of pro- and pre-biotics) on experimentally-induced acute radiation diarrhea from the perspective of mucosal inflammation and histological injury. METHODS: Ninety adult Wistar rats were randomly assigned into six groups. Group A (non-irradiated), group B (non-irradiated/synbiotic supplemented), group C (irradiated), and group D (irradiated/synbiotic supplemented) were followed up to a week after the beginning of the experiment. Group E (irradiated) and group F (irradiated/synbiotic supplemented) were followed up for four days. On the last day of the experiments tissues were harvested for structural and molecular assessments. RESULTS: Synbiotic administration could not avert the occurrence of diarrhea, but significantly attenuated its severity. This effect was associated with the significant downregulation of neutrophil accumulation and lipid peroxidation during the acute phase. During the subacute phase, synbiotic treatment significantly improved both the histological profile and radiation mucositis. These mechanisms significantly contributed to the rehabilitation of the intestinal absorptive function as further indicated from the significantly reduced weight loss. CONCLUSIONS: Given the optimization of the intestinal flora exerted by synbiotics, the resolution of diarrhea relies on the suppression of the "reactive" and the augmentation of "regenerative" components of acute radiation-induced intestinal response.
Assuntos
Diarreia/prevenção & controle , Lesões Experimentais por Radiação/complicações , Simbióticos , Adaptação Fisiológica , Animais , Diarreia/imunologia , Diarreia/patologia , Análise Discriminante , Mucosa Intestinal/patologia , Mucosa Intestinal/fisiologia , Masculino , Infiltração de Neutrófilos , Lesões Experimentais por Radiação/imunologia , Lesões Experimentais por Radiação/patologia , Ratos , Ratos WistarRESUMO
Estradiol (E2)-estrogen receptor (ER) actions are implicated in initiation, growth and progression of hormone-dependent breast cancer. Crosstalk between ERs, epidermal growth factor receptor (EGFR) and/or insulin-like growth factor receptor (IGFR) is critical for the observed resistance to endocrine therapies. Cell surface heparan sulfate proteoglycans (HSPGs) are principal mediators of cancer cell properties and the E2-ER pathway as well as those activated by EGFR and IGFR have significant roles in regulating the expression of certain cell surface HSPGs, such as syndecan-2 (SDC-2), syndecan-4 (SDC-4) and glypican-1. In this study, we therefore evaluated the role of EGFR-IGFR signaling on the constitutive expression and E2-mediated expression of ERs and HSPGs as well as the effect of E2-ERs and IGFR/EGFR-mediated cell migration in ERα+ (MCF-7) and ERß+ (MDA-MB-231) breast cancer cells using specific intracellular inhibitors of EGFR and IGFR. We report that the expression of ERα is mainly enhanced by IGFR, whereas ERß expression is mainly coordinated by EGFR. Moreover, constitutive SDC-2 expression in ERα+ and ERß+ cells is mainly mediated through the IGFR, whereas in ERα+ E2-treated cells EGFR is the active one. In contrast, SDC-4 expression is regulated by IGFR in the presence and absence of E2. E2 also seems to diminish the inhibitory effect of EGFR and IGFR inhibitors in breast cancer cell migration. These data suggest that the coordinated action of ERs with EGFR and/or IGFR is of crucial importance, providing potential targets for designing and developing novel multi-potent agents for endocrine therapies.
Assuntos
Movimento Celular/efeitos dos fármacos , Receptores ErbB/metabolismo , Estradiol/metabolismo , Receptor alfa de Estrogênio/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Sindecana-2/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Receptores ErbB/antagonistas & inibidores , Estradiol/farmacologia , Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Feminino , Regulação da Expressão Gênica , Glipicanas/genética , Glipicanas/metabolismo , Humanos , Fator de Crescimento Insulin-Like I/antagonistas & inibidores , Células MCF-7 , Quinazolinas/farmacologia , Receptor Cross-Talk , Transdução de Sinais , Sindecana-2/genética , Sindecana-4/genética , Sindecana-4/metabolismo , Tirfostinas/farmacologiaRESUMO
Cell surface heparan sulfate proteoglycans (HSPGs), syndecans and glypicans, play crucial roles in the functional properties of cancer cells, such as proliferation, adhesion, migration and invasion. Platelet-derived growth factor (PDGF)/PDGF receptor (PDGF-R) mediated signaling, on the other hand, is highly associated with cancer progression. Specifically, PDGF-Rα and PDGF-Rß expressions documented in breast cancer tissue specimens as well as breast cancer cell lines are correlated with tumor aggressiveness and metastasis. Imatinib (Glivec(®)) is a tyrosine kinase inhibitor specific for PDGF-Rs, c-ΚΙΤ and BCR-ABL. In this study we evaluated the effects of imatinib on the properties of breast cancer cells as well as on the expression of HSPGs in the presence and absence of PDGF-BB. These studies have been conducted in a panel of three breast cancer cell lines of low and high metastatic potential. Our results indicate that imatinib exerts a significant inhibitory effect on breast cancer cell proliferation, invasion and migration as well as on the cell surface expression of HSPGs even after exposure of PDGF. These effects depend on the aggressiveness of breast cancer cells and the type of HSPG. It is suggested that imatinib may be of potential therapeutic usefulness in breast cancer regimes.
Assuntos
Benzamidas/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glipicanas/metabolismo , Piperazinas/farmacologia , Pirimidinas/farmacologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Sindecana-4/metabolismo , Antineoplásicos/farmacologia , Becaplermina , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células , Citostáticos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular , Glipicanas/genética , Humanos , Mesilato de Imatinib , Ligantes , Pontos de Checagem da Fase M do Ciclo Celular , Sistema de Sinalização das MAP Quinases , Células MCF-7 , Invasividade Neoplásica/patologia , Invasividade Neoplásica/prevenção & controle , Fosforilação , Proteínas Proto-Oncogênicas c-sis/farmacologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Receptor beta de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Transdução de Sinais , Sindecana-4/genética , TranscriptomaRESUMO
Glycosaminoglycans are natural heteropolysaccharides that are present in every mammalian tissue. They are composed of repeating disaccharide units that consist of either sulfated or non-sulfated monosaccharides. Their molecular size and the sulfation type vary depending on the tissue, and their state either as part of proteoglycan or as free chains. In this regard, glycosaminoglycans play important roles in physiological and pathological conditions. During recent years, cell biology studies have revealed that glycosaminoglycans are among the key macromolecules that affect cell properties and functions, acting directly on cell receptors or via interactions with growth factors. The accumulated knowledge regarding the altered structure of glycosaminoglycans in several diseases indicates their importance as biomarkers for disease diagnosis and progression, as well as pharmacological targets. This review summarizes how the fine structural characteristics of glycosaminoglycans, and enzymes involved in their biosynthesis and degradation, are involved in cell signaling, cell function and cancer progression. Prospects for glycosaminoglycan-based therapeutic targeting in cancer are also discussed.
Assuntos
Glicosaminoglicanos/química , Glicosaminoglicanos/metabolismo , Neoplasias/fisiopatologia , Neoplasias/terapia , Sulfatos de Condroitina/química , Sulfatos de Condroitina/metabolismo , Progressão da Doença , Humanos , Ácido Hialurônico/química , Ácido Hialurônico/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Neoplasias/patologia , Transdução de Sinais/fisiologiaRESUMO
Matrix metalloproteinases (MMPs) consist of a multigene family of zinc-dependent extracellular matrix (ECM) remodeling endopeptidases implicated in pathological processes, such as carcinogenesis. In this regard, their activity plays a pivotal role in tumor growth and the multistep processes of invasion and metastasis, including proteolytic degradation of ECM, alteration of the cell-cell and cell-ECM interactions, migration and angiogenesis. The underlying premise of the current minireview is that MMPs are able to proteolytically process substrates in the extracellular milieu and, in so doing, promote tumor progression. However, certain members of the MMP family exert contradicting roles at different stages during cancer progression, depending among other factors on the tumor stage, tumor site, enzyme localization and substrate profile. MMPs are therefore amenable to therapeutic intervention by synthetic and natural inhibitors, providing perspectives for future studies. Multiple therapeutic agents, called matrix metalloproteinase inhibitors (MMPIs) have been developed to target MMPs, attempting to control their enzymatic activity. Even though clinical trials with these compounds do not show the expected results in most cases, the field of MMPIs is ongoing. This minireview critically evaluates the role of MMPs in relation to cancer progression, and highlights the challenges, as well as future prospects, for the design, development and efficacy of MMPIs.