RESUMEN
Extracellular vesicles (EVs) are a heterogenous population of plasma membrane-surrounded particles that are released in the extracellular milieu by almost all types of living cells. EVs are key players in intercellular crosstalk, both locally and systemically, given that they deliver their cargoes (consisting of proteins, lipids, mRNAs, miRNAs, and DNA fragments) to target cells, crossing biological barriers. Those mechanisms further trigger a wide range of biological responses. Interestingly, EV phenotypes and cargoes and, therefore, their functions, stem from their specific parental cells. For these reasons, EVs have been proposed as promising candidates for EV-based, cell-free therapies. One of the new frontiers of cell-based immunotherapy for the fight against refractory neoplastic diseases is represented by genetically engineered chimeric antigen receptor T (CAR-T) lymphocytes, which in recent years have demonstrated their effectiveness by reaching commercialization and clinical application for some neoplastic diseases. CAR-T-derived EVs represent a recent promising development of CAR-T immunotherapy approaches. This crosscutting innovative strategy is designed to exploit the advantages of genetically engineered cell-based immunotherapy together with those of cell-free EVs, which in principle might be safer and more efficient in crossing biological and tumor-associated barriers. In this review, we underlined the potential of CAR-T-derived EVs as therapeutic agents in tumors.
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Direct activation of the pro-apoptotic protein BAX represents a potential therapeutic strategy to trigger apoptosis in cancer. Herein, structural optimization of the reported BAX trigger site activator BTSA1 turned out into a series of pyrazolone derivatives, where compound 6d exhibited significantly enhanced antiproliferative effects and apoptosis induction ability compared to BTSA1. Mechanism of action studies revealed that compound 6d could initiate the BAX activation cascade, promoting BAX insertion into mitochondrial membranes and activating MOMP, ultimately leading to the release of cytochrome c and apoptosis. Furthermore, 6d showed significantly improved in vitro stability and CYPs profile compared to BTSA1. This work may lay a foundation to develop potent BAX trigger site activators for the treatment of BAX-expressing malignancies.
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Apoptosis , Membranas Mitocondriales , Proteína X Asociada a bcl-2/metabolismo , Membranas Mitocondriales/metabolismo , Apoptosis/fisiología , Proteínas Reguladoras de la Apoptosis/metabolismo , Citocromos c/metabolismoRESUMEN
Arylboronic acid/esters and phenyl selenides-based quinone methide (QM) precursors were reported to induce DNA interstrand crosslink (ICL) formation upon reaction with the inherently high concentrations of H2O2 in cancer cells. However, some normal cells (such as macrophages) also contain high-levels of H2O2, which may interfere with precursors' selectivity. In order to enhance the spatiotemporal specificity by the photolysis, we developed photo- and H2O2- dual-responsive DNA ICL precursors 1-3, bearing a photo-responsive coumarin moiety and a H2O2 inducible phenyl selenide group. Precursors 1-3 are efficiently activated by photoirradiation and H2O2 to generate reactive QMs crosslinking DNA. Moreover, the reactivity of precursors can be modulated by the introduction of aromatic substituents (OMe, F), and the electron donating group (OMe) displays a more pronounced promoting effect on DNA ICL formation. A subsequent piperidine heat stability study confirmed that the formed QMs primarily alkylate dAs, dGs and dCs in DNA. Furthermore, 1-3 inhibit lung cancer cell (H1299) growth by inducing DNA damage and producing toxic reactive oxygen species (ROS) upon photolysis of released coumarin. This study illustrates the potent cytotoxicity achieved by novel photo/H2O2 dual-responsive QM precursors 1-3, affording a novel strategy for the development of inducible DNA interstrand cross-linkers.
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Reactivos de Enlaces Cruzados , Peróxido de Hidrógeno , Indolquinonas , Cumarinas/química , Daño del ADN/efectos de los fármacos , Peróxido de Hidrógeno/farmacología , Indolquinonas/farmacología , Fotólisis , Reactivos de Enlaces Cruzados/química , Reactivos de Enlaces Cruzados/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Humanos , Línea Celular TumoralRESUMEN
Natural products have been an invaluable and useful source of anticancer agents over the years. Several compounds have been synthesized from natural products by modifying their structures or by using naturally occurring compounds as building blocks in the synthesis of these compounds for various purposes in different fields, such as biology, medicine, and engineering. Multiple modern and costly treatments have been applied to combat cancer and limit its lethality, but the results are not significantly refreshing. Natural products, which are a significant source of new therapeutic drugs, are currently being investigated as potential cytotoxic agents and have shown a positive trend in preclinical research and have prompted numerous innovative strategies in order to combat cancer and expedite the clinical research. Natural products are becoming increasingly important for drug discovery due to their high molecular diversity and novel biofunctionality. Furthermore, natural products can provide superior efficacy and safety due to their unique molecular properties. The objective of the current review is to provide an overview of the emergence of natural products for the treatment and prevention of cancer, such as chemosensitizers, immunotherapeutics, combinatorial therapies with other anticancer drugs, novel formulations of natural products, and the molecular mechanisms underlying their anticancer properties.
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Antineoplásicos , Productos Biológicos , Neoplasias , Humanos , Productos Biológicos/farmacología , Productos Biológicos/uso terapéutico , Productos Biológicos/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/prevención & control , Descubrimiento de DrogasRESUMEN
We aimed to identify anti-tumor agents in Quercus mongolica Fisch (QMF). Bioactive compounds in QMF leaves, which were extracted using ethanol as a co-solvent. Five point zero six grams of flavonoids were obtained from 100 g of QMF leaves. Catechin (18.4%), rutin (6.3%), ellagic acid (34.9%), quercetin (5.1%) and kaempferol (20.6%) are the main ingredients of the extracts and were further purified by HPLC. CCK-8 cell proliferation assay showed that catechin and ellagic acid exerted strong inhibitory effects on the proliferation of all cancer cells with lower IC50 values against MCF-7 human breast cancer cell lines, SMMC-7721 human hepatocellular carcinoma cells, HeLa human cervical carcinoma cell lines and SKOV3 human ovarian carcinoma cell lines (p < .05). Catechin, rutin and quercetin induced a higher rate of apoptosis and inhibited all cancer cell proliferation by inducing the G0/G1 phase and G2/M phase arrest (p < .05). However, ellagic acid induced tumor cell death, not through apoptosis and there may be other molecular mechanisms. High levels of catechin and ellagic acid in QMF can be developed as potential drugs to treat different types of cancer cells. PRACTICAL APPLICATIONS: Quercus species have been widely studied because of their antioxidant, anti-inflammatory, antimicrobial, and anti-tumor properties. Bioactive compounds in the leaves of Quercus mongolica Fisch have high levels of catechin and ellagic acid, which exert significant inhibitory properties on the proliferation of various types of cancer cells. Therefore, the bioactive compounds may be potential natural drugs in the prevention of cancer development and progression.
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Catequina , Neoplasias , Quercus , Humanos , Quercetina/farmacología , Rutina , Catequina/farmacología , Ácido Elágico , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Células HeLa , Neoplasias/tratamiento farmacológicoRESUMEN
The onset and progression of cancer are strongly associated with the dissipation of adhesion forces between cancer cells, thus facilitating their incessant attachment and detachment from the extracellular matrix (ECM) to move toward metastasis. During this process, cancer cells undergo mechanical stresses and respond to these stresses with membrane deformation while inducing protrusions to invade the surrounding tissues. Cellular response to mechanical forces is inherently related to the reorganization of the cytoskeleton, the dissipation of cell-cell junctions, and the adhesion to the surrounding ECM. Moreover, the role of focal adhesion proteins, and particularly the role of vinculin in cell attachment and detachment during migration, is critical, indicating the tight cell-ECM junctions, which favor or inhibit the metastatic cascade. The biomechanical analysis of these sequences of events may elucidate the tumor progression and the potential of cancer cells for migration and metastasis. In this work, we focused on the evaluation of the spreading rate and the estimation of the adhesion strength between breast cancer cells and ECM prior to and post-treatment with anti-tumor agents. Specifically, different tamoxifen concentrations were used for ER+ breast cancer cells, while even concentrations of trastuzumab and pertuzumab were used for HER2+ cells. Analysis of cell stiffness indicated an increased elastic Young's modulus post-treatment in both MCF-7 and SKBR-3 cells. The results showed that the post-treatment spreading rate was significantly decreased in both types of breast cancer, suggesting a lower metastatic potential. Additionally, treated cells required greater adhesion forces to detach from the ECM, thus preventing detachment events of cancer cells from the ECM, and therefore, the probability of cell motility, migration, and metastasis was confined. Furthermore, post-detachment and post-treatment vinculin levels were increased, indicating tighter cell-ECM junctions, hence limiting the probability of cell detachment and, therefore, cell motility and migration.
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Photodynamic therapy (PDT), a non-/minimally invasive cancer treatment method, has the advantages of low side effects, high selectivity, and low drug resistance. It is currently a popular cancer treatment method. However, given the shortcomings of photosensitizers such as poor photostability, poor water solubility, and short half-life inâ vivo when used alone, the development of photosensitizer nano-delivery platforms has always been a research hotspot to overcome these shortcomings. In the human body, various types of cells generally release bilayer extracellular vesicles known as exosomes. Compared with traditional materials, exosomes are currently an ideal drug delivery platform due to their homology, low immunogenicity, easy modification, high biocompatibility, and natural carrying capacity. Therefore, in this concept, we focus on the research status and prospects of engineered exosome-based photosensitizer nano-delivery platforms in cancer PDT.
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Exosomas , Neoplasias , Fotoquimioterapia , Sistemas de Liberación de Medicamentos , Humanos , Neoplasias/tratamiento farmacológico , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , SolubilidadRESUMEN
With the development of exploration for disease-related proteins or receptors, more and more novel structural lead compounds are required to designed and synthesized. The benzimidazole is an effective structural unit in which the benzene ring is fused at the 4 and 5 positions of the imidazole ring and wildly used in drug design. Here, we introduce some recent progress of research for anti-tumor agents which was target to various target proteins such as DNA topoisomerase, angiogenesis, serine/threonine protein kinase, and tyrosine protein kinase. These anti-tumor agents are all introduced benzimidazole as the structure unit. Further docking study showed that the benzimidazole group was not only act as a skeleton to expand the structure of molecule but also as an excellent ligand unit to form hydrogen bond or π-π conjugation and hydrophobic interaction with target proteins or receptors. We expect that introducing benzimidazole in the chemical structure could be a reasonable and priority strategy in novel anti-tumor agents' design.
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Antineoplásicos , Bencimidazoles , Antineoplásicos/química , Antineoplásicos/farmacología , Bencimidazoles/química , Bencimidazoles/farmacología , Diseño de Fármacos , Relación Estructura-ActividadRESUMEN
Polyphenols from olive oil are endowed with several biological activities. Chemical modifications have been recently applied to these compounds to improve their therapeutic activity in different pathological settings, including cancer. Herein, we describe the in vitro effects on multiple myeloma (MM) cells of oleil hydroxytyrosol (HTOL), a synthetic fatty ester of natural hydroxytyrosol with oleic acid. HTOL reduced the viability of various human MM cell lines (HMCLs), even when co-cultured with bone marrow stromal cells, triggering ER stress, UPR and apoptosis, while it was not cytotoxic against healthy peripheral blood mononuclear cells or B lymphocytes. Whole-transcriptome profiling of HTOL-treated MM cells, coupled with protein expression analyses, indicate that HTOL antagonizes key survival pathways for malignant plasma cells, including the undruggable IRF4-c-MYC oncogenic axis. Accordingly, c-MYC gain- and loss-of-function strategies demonstrate that HTOL anti-tumor activity was, at least in part, due to c-MYC targeting. Taken together, these findings underscore the anti-MM potential of HTOL, providing the molecular framework for further investigation of HTOL-based treatments as novel anti-cancer agents.
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Antineoplásicos/farmacología , Mieloma Múltiple/tratamiento farmacológico , Alcohol Feniletílico/análogos & derivados , Células Plasmáticas/efectos de los fármacos , Antineoplásicos/química , Línea Celular Tumoral , Humanos , Mieloma Múltiple/metabolismo , Mieloma Múltiple/patología , Alcohol Feniletílico/química , Alcohol Feniletílico/farmacología , Células Plasmáticas/metabolismo , Células Plasmáticas/patología , Transducción de Señal/efectos de los fármacosRESUMEN
Carbonic anhydrase IX (CAIX) is an enzyme expressed on the surface of cells in hypoxic tumors. It plays a role in regulation of tumor pH and promotes thus tumor cell survival and occurrence of metastases. Here, derivatives of the cobalt bis(dicarbollide)(1-) anion are reported that are based on substitution at the carbon sites of the polyhedra by two alkylsulfonamide groups differing in the length of the aliphatic connector (from C1 to C4, n=1-4), which were prepared by cobalt insertion into the 7-sulfonamidoalkyl-7,8-dicarba-nido-undecaborate ions. Pure meso- and rac-diastereoisomeric forms were isolated. The series is complemented with monosubstituted species (n=2). Synthesis by a direct method furnished similar derivatives (n=2, 3), which are chlorinated at the B(8,8') boron sites. All compounds inhibited CAIX with subnanomolar inhibition constants and showed high selectivity for CAIX. The best inhibitory properties were observed for the compound with n= 3 and two substituents present in rac-arrangement with Ki =20â pM and a selectivity index of 668. X-ray crystallography was used to study interactions of these compounds with the active site of CAIX on the structural level.
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Anhidrasa Carbónica IX/antagonistas & inhibidores , Inhibidores de Anhidrasa Carbónica/química , Cobalto/química , Complejos de Coordinación/química , Sulfonamidas/química , Sitios de Unión , Anhidrasa Carbónica IX/metabolismo , Inhibidores de Anhidrasa Carbónica/metabolismo , Inhibidores de Anhidrasa Carbónica/uso terapéutico , Dominio Catalítico , Complejos de Coordinación/metabolismo , Complejos de Coordinación/uso terapéutico , Cristalografía por Rayos X , Humanos , Conformación Molecular , Simulación del Acoplamiento Molecular , Neoplasias/tratamiento farmacológico , Neoplasias/patologíaRESUMEN
Estrogen receptor-alpha (ERα) is the target of endocrine therapies for the treatment of more than 70 % of ERα-positive breast cancers. Selective estrogen receptor degraders (SERDs) antagonize estrogen binding and target the receptor for degradation, representing the last line of treatment for resistant metastatic breast cancer patients. However, the clinical efficacy of the lone clinically approved SERD (Fulvestrant) is limited by its poor oral bioavailability. Recently, several analogues of GW5638, an acrylic acid-based ERα ligand developed by Glaxo Research Institute in 1994, have been reported as promising orally bioavailable SERDs. Some of these compounds are currently in clinical trials, while various other structurally novel SERDs have also been reported by pharma as well as academic research groups. This review provides a critical analysis of the recent developments in orally available SERDs, with a focus on the structure-activity relationships, binding interactions and pharmacokinetic properties of these compounds.
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Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Antagonistas de Estrógenos/farmacología , Receptor alfa de Estrógeno/antagonistas & inhibidores , Administración Oral , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proliferación Celular/efectos de los fármacos , Antagonistas de Estrógenos/administración & dosificación , Antagonistas de Estrógenos/química , Receptor alfa de Estrógeno/metabolismo , Femenino , Humanos , Estructura MolecularRESUMEN
Carbonic anhydrase IX (CA IX) is a transmembrane enzyme overexpressed in hypoxic tumors, where it plays an important role in tumor progression. Specific CA IX inhibitors potentially could serve as anti-cancer drugs. We designed a series of sulfonamide inhibitors containing carborane clusters based on prior structural knowledge of carborane binding into the enzyme active site. Two types of carborane clusters, 12-vertex dicarba-closo-dodecaborane and 11-vertex 7,8-dicarba-nido-undecaborate (dicarbollide), were connected to a sulfonamide moiety via aliphatic linkers of varying lengths (1-4 carbon atoms; n = 1-4). In vitro testing of CA inhibitory potencies revealed that the optimal linker length for selective inhibition of CA IX was n = 3. A 1-sulfamidopropyl-1,2-dicarba-closo-dodecaborane (3) emerged as the strongest CA IX inhibitor from this series, with a Ki value of 0.5 nM and roughly 1230-fold selectivity towards CA IX over CA II. X-ray studies of 3 yielded structural insights into their binding modes within the CA IX active site. Compound 3 exhibited moderate cytotoxicity against cancer cell lines and primary cell lines in 2D cultures. Cytotoxicity towards multicellular spheroids was also observed. Moreover, 3 significantly lowered the amount of CA IX on the cell surface both in 2D cultures and spheroids and facilitated penetration of doxorubicin. Although 3 had only a moderate effect on tumor size in mice, we observed favorable ADME properties and pharmacokinetics in mice, and preferential presence in brain over serum.
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Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Anhidrasa Carbónica IX/antagonistas & inhibidores , Inhibidores de Anhidrasa Carbónica/farmacología , Sulfonamidas/farmacología , Animales , Antígenos de Neoplasias/metabolismo , Antineoplásicos/síntesis química , Antineoplásicos/química , Neoplasias de la Mama/metabolismo , Anhidrasa Carbónica IX/metabolismo , Inhibidores de Anhidrasa Carbónica/síntesis química , Inhibidores de Anhidrasa Carbónica/química , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Perros , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones SCID , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Proteínas Recombinantes/metabolismo , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/químicaRESUMEN
The design and first enantioselective synthesis of a series of chiral ferrocifens and ferrociphenols was realised by enantioselective palladium-catalysed intramolecular direct C-H bond activation followed by McMurry coupling. Biological evaluation revealed moderate anticancer activities on breast cancer cells and evidence of chiral discrimination between enantiomers. Treatment of the novel ferrocifens with Ag2 O revealed that these systems are unable to form a neutral quinone methide, yet still demonstrate marked antiproliferative properties against both the hormone-dependent MCF-7 and hormone-independent MDA-MB-231 cell lines. This bioactivity arises from two mechanisms: Fenton-type chemistry and the anti-estrogenic activity associated with the tamoxifen-like structure.
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Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Compuestos Ferrosos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Neoplasias de la Mama/patología , Catálisis , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Compuestos Ferrosos/síntesis química , Compuestos Ferrosos/química , Humanos , Estructura Molecular , Paladio/química , Estereoisomerismo , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Doxorubicin (Dox) is a widely used antineoplastic agent that can cause heart failure. Dox cardiotoxicity is closely associated with mitochondrial damage. Mitochondrial fission and mitophagy are quality control mechanisms that normally help maintain a pool of healthy mitochondria. However, unchecked mitochondrial fission and mitophagy may compromise the viability of cardiomyocytes, predisposing them to cell death. Here, we tested this possibility by using Dox-treated H9c2 cardiac myoblast cells expressing either the mitochondria-targeted fluorescent protein MitoDsRed or the novel dual-fluorescent mitophagy reporter mt-Rosella. Dox induced mitochondrial fragmentation as shown by reduced form factor, aspect ratio, and mean mitochondrial size. This effect was abolished by short interference RNA-mediated knockdown of dynamin-related protein 1 (DRP1), a major regulator of fission. Importantly, DRP1 knockdown decreased cell death as indicated by the reduced number of propidium iodide-positive cells and the cleavage of caspase-3 and poly (ADP-ribose) polymerase. Moreover, DRP1-deficient mice were protected from Dox-induced cardiac damage, strongly supporting a role for DRP1-dependent mitochondrial fragmentation in Dox cardiotoxicity. In addition, Dox accelerated mitophagy flux, which was attenuated by DRP1 knockdown, as assessed by the mitophagy reporter mt-Rosella, suggesting the necessity of mitochondrial fragmentation in Dox-induced mitophagy. Knockdown of parkin, a positive regulator of mitophagy, dramatically diminished Dox-induced cell death, whereas overexpression of parkin had the opposite effect. Together, these results suggested that Dox cardiotoxicity was mediated, at least in part, by the increased mitochondrial fragmentation and accelerated mitochondrial degradation by the lysosome. Strategies that limit mitochondrial fission and mitophagy in the physiologic range may help reduce Dox cardiotoxicity.-Catanzaro, M. P., Weiner, A., Kaminaris, A., Li, C., Cai, F., Zhao, F., Kobayashi, S., Kobayashi, T., Huang, Y., Sesaki, H., Liang, Q. Doxorubicin-induced cardiomyocyte death is mediated by unchecked mitochondrial fission and mitophagy.
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Cardiotoxicidad/etiología , Muerte Celular/efectos de los fármacos , Doxorrubicina/farmacología , Dinámicas Mitocondriales/efectos de los fármacos , Mitofagia/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Animales , Cardiotoxicidad/metabolismo , Caspasa 3/metabolismo , Línea Celular , Dinaminas/metabolismo , Femenino , Humanos , Masculino , Ratones , Ratones Noqueados , Mitocondrias/efectos de los fármacos , Miocitos Cardíacos/metabolismo , ARN Interferente Pequeño/metabolismo , Ratas , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Deregulation of ceramide metabolism is a hallmark of human cancer. Ceramide analogues thereby represent a new class of anti-cancer agents. We aimed at developing effective and low toxic ceramide analogues and synthesized a new class of ceramide analogues starting from l-threonine. Several analogues exhibit potent cytotoxicity against human cancer cells in vitro with IC50 as low as 4.8⯵M. These ceramide analogues decreased xIAP and Bcl-xL level and exhibited significant sensitization activity to overcome human cancer cell resistance to TRAIL, a cancer-selective agent that are being tested in human clinical trials. Furthermore, we determined that these ceramide analogues effectively suppress human cancer xenograft growth in vivo with no significant toxicity at the efficacious dose. Therefore, we have developed a simple and effective method to synthesize functional ceramide analogues using l-threonine as starting material and these analogues have the great potential to be further developed as anti-cancer agents in human cancer therapy.
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Antineoplásicos/química , Antineoplásicos/farmacología , Ceramidas/química , Ceramidas/farmacología , Animales , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Ceramidas/uso terapéutico , Neoplasias del Colon/tratamiento farmacológico , Humanos , Ratones Desnudos , Neoplasias/tratamiento farmacológico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Bacteria have been investigated as anti-tumor therapeutic agents for more than a century, since Coley first observed successful curing of a patient with inoperable cancer by injection of streptococcal organisms. Previous studies have demonstrated that some obligate or facultative anaerobes can selectively accumulate and proliferate within tumors and suppress their growth. Developments in molecular biology as well as the complete genome sequencing of many bacterial species have increased the applicability of bacterial organisms for cancer treatment. In particular, the facultative anaerobe Salmonella Typhimurium has been widely studied and genetically engineered to improve its tumor-targeting ability as well as to reduce bacterial virulence. Moreover, the effectiveness of engineered attenuated S. Typhimurium strains employed as live delivery vectors of various anti-tumor therapeutic agents or combined with other therapies has been evaluated in a large number of animal experiments. The well-known S. Typhimurium mutant VNP20009 and its derivative strain TAPET-CD have even been applied in human clinical trials. However, Salmonella-mediated cancer therapies have not achieved the expected success, except in animal experiments. Many problems remain to be solved to exploit more promising strategies for combatting cancer with Salmonella bacteria. Here, we summarize the promising studies regarding cancer therapy mediated by Salmonella bacteria and highlight the main mechanisms of Salmonella anti-tumor activities.
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Antineoplásicos/uso terapéutico , Vacunas contra el Cáncer/uso terapéutico , Neoplasias/terapia , Salmonella typhimurium/inmunología , Vacunas Atenuadas/uso terapéutico , Animales , HumanosRESUMEN
Multiple myeloma (MM) is the second most common haematological malignancy. Almost all patients with MM eventually relapse, and most recommended treatment protocols for the patients with relapsed refractory MM comprise a combination of drugs with different mechanisms of action. Therefore novel drugs are in urgent need in clinic. Bcl-2 inhibitors and HDAC inhibitors were proved their anti-MM effect in clinic or under clinical trials, and they were further discovered to have synergistic interactions. In this study, a series of Bcl-2/HDAC dual-target inhibitors were designed and synthesized. Among them, compounds 7e-7g showed good inhibitory activities against HDAC6 and high binding affinities to Bcl-2 protein simultaneously. They also displayed good growth inhibitory activities against human MM cell line RPMI-8226, which proved their potential value for the treatment of multiple myeloma.
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Antineoplásicos/farmacología , Diseño de Fármacos , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/metabolismo , Mieloma Múltiple/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/química , Humanos , Modelos Moleculares , Estructura Molecular , Mieloma Múltiple/metabolismo , Mieloma Múltiple/patología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Relación Estructura-ActividadRESUMEN
ABSTRACT: A new series of 2-alkylthio-N-(quinazolin-2-yl)benzenesulfonamide derivatives have been synthesized and evaluated in vitro for their antiproliferative activity by MTT assay against cancer cell lines HCT-116, MCF-7, and HeLa as well as the NCI-60 human tumor cell lines screen. In NCI screen, three compounds inhibited approximately 50% growth of RPMI-8226 and A549/ATCC cell lines. The mean of IC50 calculated in MTT assays for three tested cell lines was about 45 µM for four compounds. The QSAR allowed finding statistically significant OPLS models for HeLa cell line. Metabolic stability in vitro studies indicated favorable and unfavorable structural elements. The good metabolic stability, with t1/2 higher than 40 min, was observed for three derivatives, which together with their antiproliferative activity and good ADMET profile, makes them good leading structures for further research.
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The tumor suppressor protein p53 is inactivated in all types of human cancers, either by negative regulation, by mutation or deletion of its gene. Specifically, in tumors that retain wild-type (wt) p53 status, p53 is inactivated by interaction with negative regulators, such as MDM2 and MDMX. These two proteins are found to be overexpressed in several different types of cancers, and the restoration of p53 activity by inhibition of these proteins is now considered an important approach for cancer treatment. The first studies using this strategy to reactivate wt p53 were focused on the development of small molecules that could inhibit MDM2. In this way, p53 could be liberated and act again as a tumor suppressor. From these studies, nine small molecules have reached clinical trials. More recently, MDMX was also identified as an important therapeutic target to efficiently reactivate wt p53, and it is now considered that, for full p53 reactivation, dual inhibition of MDM2 and MDMX is required. In this review we will focus on the most recent advances in the discovery of novel small molecules and stapled peptides that act as selective MDMX inhibitors or as dual MDM2/X inhibitors.
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Inhibidores Enzimáticos/farmacología , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas de Ciclo Celular , Inhibidores Enzimáticos/química , Humanos , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/metabolismoRESUMEN
We report herein the design and synthesis of a series of structural modified dimethylpyridazine compounds as novel hedgehog signaling pathway inhibitors. The bicyclic phthalazine core and 4-methylamino-piperidine moiety of Taladegib were replaced with dimethylpyridazine and different azacycle building blocks, respectively. The in vitro Gli-luciferase assay results demonstrate that the new scaffold still retained potent inhibitory potency. Piperidin-4-amine moiety was found to be the best linker between pharmacophores dimethylpyridazine and fluorine substituted benzoyl group. Furthermore, the optimization of 1-methyl-1H-pyrazol and 4-fluoro-2-(trifluoromethyl)benzamide by different aliphatic or aromatic rings were also investigated and the SAR were described. Several new derivatives were found to show potent Hh signaling inhibitory activity with nanomolar IC50 values. Among these compounds, compound 11c showed the highest inhibitory potency with an IC50 value of 2.33â¯nM, which was comparable to the lead compound Taladegib. In vivo efficacy of 11c in a ptch+/-p53-/- mouse medulloblastoma allograft model also indicated encouraging results.