RESUMEN

Metastasis contributes to the increased mortality rate of cancer, but the intricate mechanisms remain unclear. Cancer cells from a primary tumor invade nearby tissues and access the lymphatic or circulatory system. If these cells manage to survive and extravasate from the vasculature into distant tissues and ultimately adapt to survive, they will proliferate and facilitate malignant tumor formation. Traditional two-dimensional (2D) cell cultures offer a rapid and convenient method for validating the efficacy of anticancer drugs within a reasonable cost range, but their utility is limited because of tumors' high heterogeneity in vivo and spatial complexities. Three-dimensional (3D) cell cultures that mimic the physiological conditions of cancer cells in vivo have gained considerable interest. In these cultures, cells assemble into spheroids through gravity, magnetic forces, or their low-adhesion to the plates. Although these approaches address some of the limitations of 2D cultures, they often require a considerable amount of time and cost. Therefore, this study aims to enhance the effectiveness of 3D culture techniques by using microfluidic systems to provide a high-throughput and sensitive pipeline for drug screening. Using these systems, we studied the effects of lanthanide elements, which have garnered interest in cancer treatment, on spheroid formation and cell spreading. Our findings suggest that these elements alter the compactness of cell spheroids and decrease cell mobility.

Asunto(s)

Elementos de la Serie de los Lantanoides , Esferoides Celulares , Esferoides Celulares/efectos de los fármacos , Humanos , Elementos de la Serie de los Lantanoides/toxicidad , Elementos de la Serie de los Lantanoides/farmacología , Técnicas de Cultivo de Célula/métodos , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/toxicidad , Técnicas Analíticas Microfluídicas/instrumentación , Técnicas Analíticas Microfluídicas/métodos , Supervivencia Celular/efectos de los fármacos , Técnicas de Cultivo Tridimensional de Células/métodos , Ensayos de Selección de Medicamentos Antitumorales/métodos

RESUMEN

Due to their exceptional physicochemical features, green synthesized silver nanoparticles (AgNPs) have been of considerable interest in cancer treatment. In the present study, for the first time, we aimed to green synthesize AgNPs from Euphorbia retusa and explore their anticancer potential on human breast cancer (MCF-7) cells. First, the green synthesized AgNPs (EU-AgNPs) were well characterized by UV-visible spectroscopy, Fourier transmission infrared (FTIR) spectrum, XRD, scanning and transmission electron microscopy (SEM and TEM), and EDX techniques. The characterization data exhibited that EU-AgNPs were spherical in shape and crystalline in nature with an average size of 17.8 nm. FTIR results established the presence of active metabolites in EU-AgNPs. Second, the anticancer effect of EU-AgNPs was evaluated against MCF-7 cells by MTT and neutral red uptake (NRU) assays. Moreover, morphological changes, ROS production, MMP, and apoptotic marker genes were also studied upon exposure to cytotoxic doses of EU-AgNPs. Our results showed that EU-AgNPs induce cytotoxicity in a concentration-dependent manner, with an IC50 value of 40 µg/mL. Morphological changes in MCF-7 cells exposed to EU-AgNPs also confirm their cytotoxic effects. Increased ROS and decreased MMP levels revealed that EU-AgNPs induced oxidative stress and mitochondrial membrane dysfunction. Moreover, ROS-mediated apoptosis was confirmed by elevated levels of proapoptotic marker genes (p53, Bax, caspase-3, and caspase-9) and reduced levels of an antiapoptotic gene (Bcl-2). Altogether, these findings suggested that EU-AgNPs could induce potential anticancer effects through ROS-mediated apoptosis in MCF-7 cells.

Asunto(s)

Antineoplásicos , Apoptosis , Neoplasias de la Mama , Tecnología Química Verde , Nanopartículas del Metal , Mitocondrias , Especies Reactivas de Oxígeno , Plata , Humanos , Plata/química , Plata/farmacología , Nanopartículas del Metal/química , Apoptosis/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Células MCF-7 , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/tratamiento farmacológico , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Femenino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Euphorbia/química , Relación Dosis-Respuesta a Droga , Supervivencia Celular/efectos de los fármacos

RESUMEN

Introduction: Infantile Hemangioma (IH) is a prevalent benign vascular tumor affecting approximately 5-10% of infants. Its underlying pathogenesis remains enigmatic, and current therapeutic approaches show limited effectiveness. Our study aimed to discover potential IH-associated therapeutics through a transcriptomic, computational drug repurposing methodology. Methods: Utilizing the IH-specific dataset GSE127487 from the Gene Expression Omnibus, we identified differentially expressed genes (DEGs) and conducted weighted gene coexpression network analysis (WGCNA). Subsequently, a protein-protein interaction (PPI) network was constructed to obtain the top 100 hub genes. Drug candidates were sourced from the Connectivity Map (CMap) and Comparative Toxicogenomics Database (CTD). Results: Our analysis revealed 1203 DEGs and a significant module of 1780 mRNAs strongly correlated with IH. These genes were primarily enriched in the PI3K/AKT/MTOR, RAS/MAPK, and CGMP/PKG signaling pathway. After creating a PPI network of overlapping genes, we filtered out the top 100 hub genes. Ultimately, 44 non-toxic drugs were identified through the CMap and CTD databases. Twelve molecular-targeting agents (belinostat, chir 99021, dasatinib, entinostat, panobinostat, sirolimus, sorafenib, sunitinib, thalidomide, U 0126, vorinostat, and wortmannin) may be potential candidates for IH therapy. Moreover, in vitro experiments demonstrated that entinostat, sorafenib, dasatinib, and sirolimus restricted the proliferation and migration and initiated apoptosis in HemEC cells, thereby underscoring their potential therapeutic value. Conclusion: Our investigation revealed that the pathogenic mechanism underlying IH might be closely associated with the PI3K/AKT/MTOR, RAS/MAPK, and CGMP/PKG signaling pathways. Furthermore, we identified twelve molecular-targeting agents among the predicted drugs that show promise as therapeutic candidates for IH.

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Transcriptomic analysis used to discover potential therapeutics for Infantile Hemangioma (IH). Key IH-related pathways: PI3K/AKT/MTOR, RAS/MAPK, and CGMP/PKG signaling identified. Identified 44 non-toxic drugs as potential IH therapies via CMap and CTD. Twelve molecular agents show potential as IH therapy candidates. In vitro studies confirmed entinostat, sorafenib, dasatinib, and sirolimus inhibit HemEC cell proliferation and induce apoptosis.

Asunto(s)

Antineoplásicos , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Hemangioma , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Hemangioma/tratamiento farmacológico , Hemangioma/patología , Hemangioma/genética , Proliferación Celular/efectos de los fármacos , Lactante , Simulación por Computador , Apoptosis/efectos de los fármacos , Mapas de Interacción de Proteínas/efectos de los fármacos , Reposicionamiento de Medicamentos , Relación Dosis-Respuesta a Droga

Asunto(s)

Proteínas Adaptadoras Transductoras de Señales , Proteínas con Dominio LIM , Neoplasias de la Boca , Transducción de Señal , Humanos , Transducción de Señal/efectos de los fármacos , Proteínas con Dominio LIM/metabolismo , Proteínas con Dominio LIM/antagonistas & inhibidores , Neoplasias de la Boca/tratamiento farmacológico , Neoplasias de la Boca/metabolismo , Neoplasias de la Boca/patología , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/antagonistas & inhibidores , Proteínas del Citoesqueleto/metabolismo , Proteínas del Citoesqueleto/antagonistas & inhibidores , Antineoplásicos/farmacología , Antineoplásicos/química , Quinasas Janus/antagonistas & inhibidores , Quinasas Janus/metabolismo , Proliferación Celular/efectos de los fármacos , Factores de Transcripción STAT/metabolismo , Factores de Transcripción STAT/antagonistas & inhibidores , Progresión de la Enfermedad , Ensayos de Selección de Medicamentos Antitumorales

RESUMEN

Rho family GTPases regulate cellular processes and promote tumour growth and metastasis; thus, RhoA is a potential target for tumour metastasis inhibition. However, limited progress has been made in the development of RhoA targeting anticancer drugs. Here, we synthesised benzo[b]thiophene-3-carboxylic acid 1,1-dioxide derivatives based on a covalent inhibitor of RhoA (DC-Rhoin), reported in our previous studies. The observed structure-activity relationship (contributed by carboxamide in C-3 and 1-methyl-1H-pyrazol in C-5) enhanced the anti-proliferative activity of the derivatives. Compound b19 significantly inhibited the proliferation, migration, and invasion of MDA-MB-231 cells and promoted their apoptosis. The suppression of myosin light chain phosphorylation and the formation of stress fibres confirmed the inhibitory activity of b19 via the RhoA/ROCK pathway. b19 exhibited a different binding pattern from DC-Rhoin, as observed in molecular docking analysis. This study provides a reference for the development of anticancer agents targeting the RhoA/ROCK pathway.

Asunto(s)

Antineoplásicos , Apoptosis , Proliferación Celular , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Tiofenos , Quinasas Asociadas a rho , Proteína de Unión al GTP rhoA , Humanos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Quinasas Asociadas a rho/antagonistas & inhibidores , Quinasas Asociadas a rho/metabolismo , Proteína de Unión al GTP rhoA/metabolismo , Proteína de Unión al GTP rhoA/antagonistas & inhibidores , Relación Estructura-Actividad , Proliferación Celular/efectos de los fármacos , Estructura Molecular , Apoptosis/efectos de los fármacos , Tiofenos/farmacología , Tiofenos/química , Tiofenos/síntesis química , Movimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Simulación del Acoplamiento Molecular

RESUMEN

Pyridazinone derivatives have been extensively used as anticancer agents. IMB5036 is a structure specific pyridazinone compound with potential antitumor activity via targeting KSRP protein which controls gene expression at multiple levels. In this study, fifteen IMB5036 analogues were synthesized and preliminary structure-activity relationships were explored. Among them, compounds 8 and 10 exhibited remarkably anti-proliferation of various cancer cells and a good cancer cell selectivity (against human fetal hepatocyte L02 cells). More detailed investigation was included that both 8 and 10 inhibited colony formation and migration in concentration-dependent mode against MCF-7 cells. Additionally, 8 and 10 induced apoptosis and cell cycle arrest, decreased mitochondrial membrane potential, damaged DNA, and increased reactive oxygen species. Moreover, 8 displayed a potent antitumor efficacy (TGI = 74.2 %, at a dose of 30 mg/kg) in MCF-7 xenograft model by i.p. injection. Further, we synthesized a biotinylated probe 16 for identifying the detail domain of KSRP. Through pull down assay and molecular docking study, we validated that the KH23 domain functioned as the binding pocket for the compounds. Thus, compound 8 was identified as a novel targeting KSRP pyridazinone-based compound and exhibited excellent antitumor activity both in vitro and in vivo.

Asunto(s)

Antineoplásicos , Apoptosis , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Piridazinas , Humanos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Piridazinas/farmacología , Piridazinas/química , Piridazinas/síntesis química , Proliferación Celular/efectos de los fármacos , Relación Estructura-Actividad , Animales , Apoptosis/efectos de los fármacos , Ratones , Estructura Molecular , Relación Dosis-Respuesta a Droga , Simulación del Acoplamiento Molecular , Femenino , Ratones Desnudos , Ratones Endogámicos BALB C , Línea Celular Tumoral

RESUMEN

Tumor proliferation and metastasis are intricately linked to blood vessel formation, with vascular endothelial growth factor (VEGF) playing a pivotal role in orchestrating angiogenesis throughout tumor progression. Pseudolaric acid B (PAB) has emerged as a potent inhibitor of tumor cell proliferation, migration, and angiogenesis. In efforts to enhance its efficacy, 37 derivatives of PAB were synthesized and assessed for their capacity to suppress VEGF secretion in SiHa cells under hypoxic conditions. Notably, majority of these derivatives exhibited significant inhibition of VEGF protein secretion without inducing cytotoxicity. Among them, compound M2 displayed the most potent inhibitory activity, with an IC50 value of 0.68 µM, outperforming the lead compound PAB (IC50 = 5.44 µM). Compound M2 not only curbed the migration and angiogenesis of HUVECs under hypoxic conditions but also hindered the invasion of SiHa cells. Mechanistic investigations unveiled that compound M2 may impede the accumulation and nuclear translocation of hypoxia-inducible factor 1α (HIF-1α) in SiHa cells, thereby downregulating VEGF expression. This inhibitory effect on HIF-1α was corroborated by experiments utilizing the protease inhibitor MG-132 and protein synthesis inhibitor CHX, indicating that compound M2 diminishes HIF-1α levels by reducing its synthesis. Furthermore, compound M2 was observed to modulate the PI3K/AKT/mTOR and MAPK signaling pathways in tumor cells, thereby regulating HIF-1α translation and synthesis. In vivo studies demonstrated that compound M2 exhibited low toxicity and effectively curbed tumor growth. Immunohistochemistry analyses validated that compound M2 effectively suppressed the expression of HIF-1α and VEGF in tumor tissues, underscoring its potential as a promising therapeutic agent for targeting tumor angiogenesis.

Asunto(s)

Inhibidores de la Angiogénesis , Antineoplásicos , Proliferación Celular , Diterpenos , Diseño de Fármacos , Subunidad alfa del Factor 1 Inducible por Hipoxia , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Factor A de Crecimiento Endotelial Vascular , Humanos , Factor A de Crecimiento Endotelial Vascular/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/síntesis química , Inhibidores de la Angiogénesis/química , Proliferación Celular/efectos de los fármacos , Relación Estructura-Actividad , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/antagonistas & inhibidores , Diterpenos/farmacología , Diterpenos/síntesis química , Diterpenos/química , Transducción de Señal/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Estructura Molecular , Relación Dosis-Respuesta a Droga , Línea Celular Tumoral , Animales , Movimiento Celular/efectos de los fármacos , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/metabolismo

RESUMEN

Both boron neutron capture therapy (BNCT) and photothermal therapy (PTT) have been applied to tumor treatment in clinical. However, their therapeutic efficacy is limited. For BNCT, the agents not only exhibit poor targeting ability but also permit only a single irradiation session within a course due to significant radiation risks. In the context of PTT, despite enhanced selectivity, the limited photothermal effect fails to meet clinical demands. Hence, the imperative arises to combine these two therapies to enhance tumor-killing capabilities and improve the targeting of BNCT agents by leveraging the advantages of PTT agents. In this study, we synthesized a potential responsive agent by linking 4-mercaptophenylboronic acid (MPBA) and IR-780 dye that served as the agents for BNCT and PTT, respectively, which possesses the dual capabilities of photothermal effects and thermal neutron capture. Results from both in vitro and in vivo research demonstrated that IR780-MPBA effectively inhibits tumor growth through its photothermal effect with no significant toxicity. Furthermore, IR780-MPBA exhibited substantial accumulation in tumor tissues and superior tumor-targeting capabilities compared with MPBA, which demonstrated that IR780-MPBA possesses significant potential as a combined antitumor therapy of PTT and BNCT, presenting a promising approach for antitumor treatments.

Asunto(s)

Antineoplásicos , Terapia por Captura de Neutrón de Boro , Terapia Fototérmica , Animales , Ratones , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Tamaño de la Partícula , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Materiales Biocompatibles/síntesis química , Ensayos de Selección de Medicamentos Antitumorales , Ensayo de Materiales , Supervivencia Celular/efectos de los fármacos , Indoles/química , Indoles/farmacología , Proliferación Celular/efectos de los fármacos , Estructura Molecular , Línea Celular Tumoral , Ratones Endogámicos BALB C , Ácidos Borónicos/química , Ácidos Borónicos/farmacología , Femenino

RESUMEN

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and STAT3 has emerged as an effective drug target for TNBC treatment. Herein, we employed a scaffold-hopping strategy of natural products to develop a series of naphthoquinone-furopiperidine derivatives as novel STAT3 inhibitors. The in vitro assay showed that compound 10g possessed higher antiproliferative activity than Cryptotanshinone and Napabucasin against TNBC cell lines, along with lower toxicity and potent antitumor activity in a TNBC xenograft model. Mechanistically, 10g could inhibit the phosphorylation of STAT3 and the binding affinity was determined by the SPR assay (KD = 8.30 µM). Molecule docking studies suggested a plausible binding mode between 10g and the SH2 domain, in which the piperidine fragment and the terminal hydroxy group of 10g played an important role in demonstrating the success of this evolution strategy. These findings provide a natural product-inspired novel STAT3 inhibitor for TNBC treatment.

Asunto(s)

Antineoplásicos , Productos Biológicos , Proliferación Celular , Simulación del Acoplamiento Molecular , Naftoquinonas , Piperidinas , Factor de Transcripción STAT3 , Neoplasias de la Mama Triple Negativas , Factor de Transcripción STAT3/antagonistas & inhibidores , Factor de Transcripción STAT3/metabolismo , Humanos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Naftoquinonas/farmacología , Naftoquinonas/química , Naftoquinonas/síntesis química , Naftoquinonas/uso terapéutico , Productos Biológicos/farmacología , Productos Biológicos/química , Productos Biológicos/síntesis química , Piperidinas/farmacología , Piperidinas/química , Piperidinas/síntesis química , Piperidinas/uso terapéutico , Animales , Femenino , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ratones , Relación Estructura-Actividad , Ratones Desnudos , Ensayos Antitumor por Modelo de Xenoinjerto , Descubrimiento de Drogas , Ratones Endogámicos BALB C , Ensayos de Selección de Medicamentos Antitumorales

RESUMEN

A series of new gold(I) and silver(I) N-heterocyclic carbenes bearing a 1-thio-ß-d-glucose tetraacetate moiety was synthesized and chemically characterized. The compounds' stability and solubility in physiological conditions were investigated employing a multitechnique approach. Interaction studies with biologically relevant proteins, such as superoxide dismutase (SOD) and human serum albumin (HSA), were conducted via UV-vis absorption spectroscopy and high-resolution ESI mass spectrometry. The biological activity of the compounds was evaluated in the A2780 and A2780R (cisplatin-resistant) ovarian cancer cell lines and the HSkMC (human skeletal muscle) healthy cell line. Inhibition studies of the selenoenzyme thioredoxin reductase (TrxR) were also carried out. The results highlighted that the gold complexes are more stable in aqueous environment and capable of interaction with SOD and HSA. Moreover, these carbenes strongly inhibited the TrxR activity. In contrast, the silver ones underwent structural alterations in the aqueous medium and showed greater antiproliferative activity.

Asunto(s)

Antineoplásicos , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Oro , Compuestos Heterocíclicos , Metano , Plata , Reductasa de Tiorredoxina-Disulfuro , Humanos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Plata/química , Plata/farmacología , Oro/química , Oro/farmacología , Metano/análogos & derivados , Metano/química , Metano/farmacología , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Compuestos Heterocíclicos/síntesis química , Proliferación Celular/efectos de los fármacos , Reductasa de Tiorredoxina-Disulfuro/antagonistas & inhibidores , Reductasa de Tiorredoxina-Disulfuro/metabolismo , Interacciones Hidrofóbicas e Hidrofílicas , Estructura Molecular , Relación Estructura-Actividad , Línea Celular Tumoral , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa/antagonistas & inhibidores

RESUMEN

The activation of cellular ferroptosis is promising in tumor therapy. However, ferroptosis is parallelly inhibited by antiferroptotic substances, including glutathione peroxidase 4 (GPX4), dihydroorotate dehydrogenase (DHODH), and ferroptosis suppressor protein 1 (FSP1). Thus, it is highly desirable, yet challenging, to simultaneously suppress these three antiferroptotic substances for activating ferroptosis. Here, we rationally designed a hollow iron-doped SiO2-based nanozyme (FeSHS) loaded with brequinar (BQR) and lificiguat (YC-1), named FeSHS/BQR/YC-1-PEG, for tumor ferroptosis activation. FeSHS were developed through the continuous etching of SiO2 nanoparticles by iron ions, which exhibit pH/glutathione-responsive biodegradability, along with mimicking the activities of peroxidase, glutathione oxidase, and NAD(P)H oxidase. Specifically, glutathione depletion and NAD(P)H oxidation by FeSHS will suppress the expression of GPX4 and inhibit FSP1 by disrupting the NAD(P)H/FSP1/ubiquinone axis. In addition, the released BQR can suppress the expression of DHODH. Meanwhile, YC-1 is able to increase the cellular polyunsaturated fatty acids (PUFAs) by destroying the HIF-1α/lipid droplet axis. The elevation of levels of iron and PUFAs while simultaneously disrupting the GPX4/DHODH/FSP1 inhibitory pathways by our designed nanoplatform displayed high therapeutic efficacy both in vitro and in vivo. This work elucidates rationally designing smart nanoplatforms for ferroptosis activation and future tumor treatments.

Asunto(s)

Neoplasias de la Mama , Ferroptosis , Hierro , Dióxido de Silicio , Dióxido de Silicio/química , Ferroptosis/efectos de los fármacos , Humanos , Animales , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Ratones , Hierro/química , Hierro/metabolismo , Femenino , Antineoplásicos/farmacología , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Ratones Endogámicos BALB C , Ensayos de Selección de Medicamentos Antitumorales , Nanopartículas/química

RESUMEN

Liposomes are applied to various anticancer treatments as representative drug delivery carriers. However, liposomes do not have their own targeting properties; therefore, there are limitations in drug delivery to specific tissues or cells. High targetability in drug delivery is an important factor in improving bioavailability and drug efficacy and reducing side effects; recent research has been actively investigated to modify the surface of liposomes to give them specific functions. In this study, we studied a drug delivery system for anticancer treatment that enhances targeting ability through fusion with exosomes on the surface of liposomes. We designed exosome-liposome hybrid nanoparticles loaded with a gemcitabine prodrug as a treatment for pancreatic ductal adenocarcinoma (PDAC). Membrane fusion with exosomes shows excellent targeting ability to pancreatic cancer cells due to intrinsic targeting ability and expansion of the macropinocytosis pathway.

Asunto(s)

Carcinoma Ductal Pancreático , Desoxicitidina , Ensayos de Selección de Medicamentos Antitumorales , Vesículas Extracelulares , Gemcitabina , Liposomas , Nanopartículas , Neoplasias Pancreáticas , Tamaño de la Partícula , Profármacos , Desoxicitidina/análogos & derivados , Desoxicitidina/química , Desoxicitidina/farmacología , Profármacos/química , Profármacos/farmacología , Humanos , Liposomas/química , Nanopartículas/química , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/metabolismo , Vesículas Extracelulares/química , Vesículas Extracelulares/metabolismo , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/metabolismo , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Proliferación Celular/efectos de los fármacos , Ensayo de Materiales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Sistemas de Liberación de Medicamentos , Antineoplásicos/química , Antineoplásicos/farmacología

RESUMEN

Using the principle of "Magic Bullet", a cisplatin-derived platinum(IV) prodrug heterobimetallic Pt(IV)-Ru(II) complex, cis,cis,trans-[Pt(NH3)2Cl2{Ru(tpy-BODIPY)(tpy-COO)}(biotin)]Cl2 (Pt-Ru-B, 2), having two axial ligands, namely, biotin as water-soluble B-vitamin for enhanced cellular uptake and a BODIPY-ruthenium(II) (Ru-B, 1) photosensitizer having N,N,N-donor tpy (4'-phenyl-2,2':6',2″-terpyridine) bonded to boron-dipyrromethene (BODIPY), is developed as a "Platin Bullet" for targeted photodynamic therapy (PDT). Pt-Ru-B exhibited intense absorption near 500 nm and emission near 513 nm (λex = 488 nm) in a 10% dimethyl sulfoxide-Dulbecco's phosphate-buffered saline medium (pH 7.2). The BODIPY complex on light activation generates singlet oxygen as the reactive oxygen species (ROS) giving a quantum yield (ΦΔ) of ∼0.64 from 1,3-diphenylisobenzofuran experiments. Pt-Ru-B exhibited preferential cellular uptake in cancer cells over noncancerous cells. The dichlorodihydrofluorescein diacetate assay confirmed the generation of cellular ROS. Confocal images revealed its mitochondrial internalization. Pt-Ru-B showed submicromolar photocytotoxicity in visible light (400-700 nm) in A549 and multidrug-resistant MDA-MB-231 cancer cells. It remained nontoxic in the dark and less toxic in nontumorigenic cells. Cellular apoptosis and alteration of the mitochondrial membrane potential were evidenced from the respective Annexin V-FITC/propidium iodide assay and JC-1 dye assay. A wound healing assay using A549 cells and Pt-Ru-B revealed inhibition of cancer cell migration, highlighting its potential as an antimetastatic agent.

Asunto(s)

Antineoplásicos , Biotina , Fotoquimioterapia , Fármacos Fotosensibilizantes , Profármacos , Rutenio , Humanos , Profármacos/farmacología , Profármacos/química , Profármacos/síntesis química , Rutenio/química , Rutenio/farmacología , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Biotina/química , Biotina/farmacología , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Compuestos de Boro/química , Compuestos de Boro/farmacología , Compuestos de Boro/síntesis química , Porfobilinógeno/análogos & derivados , Porfobilinógeno/química , Porfobilinógeno/farmacología , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Platino (Metal)/química , Platino (Metal)/farmacología , Estructura Molecular , Supervivencia Celular/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Apoptosis/efectos de los fármacos , Cisplatino/farmacología , Cisplatino/química

RESUMEN

Cancer continues to be a major global health issue, ranking among the top causes of death worldwide. To develop novel antitumor agents, this study focused on the synthesis of a series of 21 novel furanopyridinone derivatives through structural modifications and functional enhancements. The in vitro anti-tumor activities of these compounds were investigated through the cytotoxicity against KYSE70 and KYSE150 and led to the identification of compound 4c as the most potent compound. At a concentration of 20 µg/mL, compound 4c demonstrated a remarkable 99% inhibition of KYSE70 and KYSE150 cell growth after 48 h. IC50 was 0.655 µg/mL after 24 h. Additionally, potential anti-tumor cellular mechanisms were explored through molecular docking, which was used to predict the binding mode of 4c with METAP2 and EGFR, suggesting that the C=O part of the pyridone moiety likely played a crucial role in binding. This study provided valuable insights and guidance for the development of novel anticancer drugs with novel structural scaffolds.

Asunto(s)

Antineoplásicos , Proliferación Celular , Neoplasias Esofágicas , Simulación del Acoplamiento Molecular , Piridonas , Humanos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Piridonas/farmacología , Piridonas/química , Piridonas/síntesis química , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/metabolismo , Proliferación Celular/efectos de los fármacos , Relación Estructura-Actividad , Ensayos de Selección de Medicamentos Antitumorales , Apoptosis/efectos de los fármacos

RESUMEN

In the following study, a series of new lupeol-3-carbamate derivatives were synthesized, and the structures of all the newly derived compounds were characterized. The new compounds were screened to determine their anti-proliferative activity against human lung cancer cell line A549, human liver cancer cell line HepG2, and human breast cancer cell line MCF-7. Most of the compounds were found to show better anti-proliferative activity in vitro than lupeol. Among them, obvious anti-proliferation activity (IC50 = 5.39~9.43 µM) was exhibited by compound 3i against all three tumor cell lines. In addition, a salt reaction was performed on compound 3k (IC50 = 13.98 µM) and it was observed that the anti-proliferative activity and water solubility of compound 3k·CH3I (IC50 = 3.13 µM), were significantly enhanced subsequent to the salt formation process. The preliminary mechanistic studies demonstrated that apoptosis in HepG2 cells was induced by compound 3k·CH3I through the inhibition of the PI3K/AKT/mTOR pathway. In conclusion, a series of new lupeol-3-carbamate derivatives were synthesized via the structural modification of the C-3 site of lupeol, thus laying a theoretical foundation for the design of this new anticancer drug.

Asunto(s)

Antineoplásicos , Apoptosis , Carbamatos , Proliferación Celular , Triterpenos Pentacíclicos , Humanos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Triterpenos Pentacíclicos/farmacología , Triterpenos Pentacíclicos/síntesis química , Triterpenos Pentacíclicos/química , Proliferación Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Carbamatos/farmacología , Carbamatos/química , Carbamatos/síntesis química , Células Hep G2 , Relación Estructura-Actividad , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Células A549 , Células MCF-7 , Proteínas Proto-Oncogénicas c-akt/metabolismo , Estructura Molecular , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Lupanos

RESUMEN

The reaction between glycine-type aminonaphthol derivatives substituted with 2- or 1-naphthol and indole or 7-azaindole has been tested. Starting from 2-naphthol as a precursor, the reaction led to the formation of ring-closed products, while in the case of a 1-naphthol-type precursor, the desired biaryl ester was isolated. The synthesis of a bifunctional precursor starting from 5-chloro-8-hydroxyquinoline, morpholine, and ethyl glyoxylate via modified Mannich reaction is reported. The formed Mannich base 10 was subjected to give bioconjugates with indole and 7-azaindole. The effect of the aldehyde component and the amine part of the Mannich base on the synthetic pathway was also investigated. In favor of having a preliminary overview of the structure-activity relationships, the derivatives have been tested on cancer and normal cell lines. In the case of bioconjugate 16, as the most powerful scaffold in the series bearing indole and a 5-chloro-8-hydroxyquinoline skeleton, a potent toxic activity against the resistant Colo320 colon adenocarcinoma cell line was observed. Furthermore, this derivative was selective towards cancer cell lines showing no toxicity on non-tumor fibroblast cells.

Asunto(s)

Antineoplásicos , Indoles , Humanos , Indoles/química , Indoles/farmacología , Indoles/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Relación Estructura-Actividad , Oxiquinolina/química , Oxiquinolina/farmacología , Metano/química , Metano/análogos & derivados , Estructura Molecular , Ensayos de Selección de Medicamentos Antitumorales

RESUMEN

Annonaceous acetogenins (ACGs) have great potential in the treatment of gliomas, but are extremely insoluble and difficult for delivery in vivo. Poly(ethylene oxide)-b-poly(butylene oxide) (PEO-PBO) is an amphiphilic polymer and can reduce the clearance of nanoparticles by mononuclear phagocyte system. To explore an efficient and safe nanomedicine for glioma, ACGs-loaded nanomicelles (ACGs/EB-NCs) was constructed using PEO-PBO as a carrier, and the effect of PEO-PBO content on the targeting and anti-glioma activity were also compared. ACGs/EB5-NCs, ACGs/EB10-NCs and ACGs/EB20-NCs, the three nanomicellels prepared with different ACGs/EB feeding ratios, had average particle sizes of 148.8±0.5 nm, 32.7±4.1 nm, and 27.1±0.3 nm, respectively. The three ACGs/EB-NCs were spherical in shape, with drug loading content close to the theoretical drug loading content, encapsulation efficiency greater than 97 %, and good stability in physiological media. The cumulative release rates of ACGs/EB5-NCs, ACGs/EB10-NCs and ACGs/EB20-NCs were 78.2 %, 63.4 %, and 56.3 % within 216 hours, respectively. The inhibitory effects of three ACGs/EB-NCs on U87 MG cells were similar and stronger than free ACGs (P<0.05), with half inhibitory concentration of 0.17, 0.18, and 0.16 ng/mL (P>0.05), respectively. In U87 MG tumor­bearing mice, ACGs/EB5-NC, ACGs/EB10-NCs and ACGs/EB20-NCs showed a similar tumor inhibition rate of 61.1±5.9 %, 56.2±8.6 % and 64.3±9.4 % (P>0.05), with good safety. Three ACGs/EB-NCs exhibited excellent liver escape ability and tumor targeting ability, with the tumor targeting index greater than 1.5. Three ACGs/EB-NCs were successfully prepared with strong anti-glioma activity and tumor targeting properties, which are expected to provide new options for the clinical treatment of gliomas. The content of PEO-PBO in micelles did not have a significant effect on the tumor targeting and anti-glioma activity of ACGs/EB-NCs.

Asunto(s)

Acetogeninas , Glioma , Micelas , Nanopartículas , Polietilenglicoles , Glioma/tratamiento farmacológico , Glioma/patología , Animales , Acetogeninas/química , Acetogeninas/farmacología , Polietilenglicoles/química , Humanos , Ratones , Nanopartículas/química , Tamaño de la Partícula , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/química , Butileno Glicoles/química , Butileno Glicoles/farmacología , Proliferación Celular/efectos de los fármacos , Ratones Endogámicos BALB C , Supervivencia Celular/efectos de los fármacos , Ratones Desnudos , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Portadores de Fármacos/química , Ensayos de Selección de Medicamentos Antitumorales

RESUMEN

Oral squamous cell carcinoma (OSCC) is highly heterogeneous and aggressive, but therapies based on single-targeted nanoparticles frequently address these tumors as a single illness. To achieve more efficient drug transport, it is crucial to develop nanodrug-carrying systems that simultaneously target two or more cancer biomarkers. In addition, combining chemotherapy with near-infrared (NIR) light-mediated thermotherapy allows the thermal ablation of local malignancies via photothermal therapy (PTT), and triggers drug release to improve chemosensitivity. Thus, a novel dual-targeted nano-loading system, DOX@GO-HA-HN-1 (GHHD), was created for synergistic chemotherapy and PTT by the co-modification of carboxylated graphene oxide (GO) with hyaluronic acid (HA) and HN-1 peptide and loading with the anticancer drug doxorubicin (DOX). Targeted delivery using GHHD was shown to be superior to single-targeted nanoparticle delivery. NIR radiation will encourage the absorption of GHHD by tumor cells and cause the site-specific release of DOX in conjunction with the acidic microenvironment of the tumor. In addition, chemo-photothermal combination therapy for cancer treatment was realized by causing cell apoptosis under the irradiation of 808-nm laser. In summary, the application of GHHD to chemotherapy combined with photothermal therapy for OSCC is shown to have important potential as a means of combatting the low accumulation of single chemotherapeutic agents in tumors and drug resistance generated by single therapeutic means, enhancing therapeutic efficacy.

Asunto(s)

Carcinoma de Células Escamosas , Doxorrubicina , Sistemas de Liberación de Medicamentos , Grafito , Rayos Infrarrojos , Neoplasias de la Boca , Doxorrubicina/farmacología , Doxorrubicina/química , Humanos , Neoplasias de la Boca/tratamiento farmacológico , Neoplasias de la Boca/patología , Neoplasias de la Boca/terapia , Grafito/química , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/terapia , Concentración de Iones de Hidrógeno , Portadores de Fármacos/química , Nanopartículas/química , Liberación de Fármacos , Animales , Apoptosis/efectos de los fármacos , Antibióticos Antineoplásicos/farmacología , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/administración & dosificación , Proliferación Celular/efectos de los fármacos , Terapia Fototérmica , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Ácido Hialurónico/química , Supervivencia Celular/efectos de los fármacos , Ratones , Tamaño de la Partícula , Propiedades de Superficie

RESUMEN

In the realm of intracellular drug delivery, overcoming the barrier of endosomal entrapment stands as a critical factor influencing the effectiveness of nanodrug delivery systems. This study focuses on the synthesis of an acid-sensitive fatty acid derivative called imidazole-stearic acid (IM-SA). Leveraging the proton sponge effect attributed to imidazole groups, IM-SA was anticipated to play a pivotal role in facilitating endosomal escape. Integrated into the lipid core of solid lipid nanoparticles (SLNs), IM-SA was paired with hyaluronic acid (HA) coating on the surface of SLNs loading with curcumin (CUR). The presence of IM-SA and HA endowed HA-IM-SLNs@CUR with dual functionalities, enabling the promotion of endosomal escape, and specifical targeting of liver cancer. HA-IM-SLNs@CUR exhibited a particle size of ∼228 nm, with impressive encapsulation efficiencies (EE) of 87.5 % ± 2.3 % for CUR. Drugs exhibit significant pH sensitive release behavior. Cellular experiments showed that HA-IM-SLN@CUR exhibits enhanced drug delivery capability. The incorporation of IM-SA significantly improved the endosomal escape of HA-IM-SLN@CUR, facilitating accelerated intracellular drug release and increasing intracellular drug concentration, exhibiting excellent growth inhibitory effects on HepG2 cells. Animal experiments revealed a 3.4-fold increase in CUR uptake at the tumor site with HA-IM-SLNs@CUR over the free CUR, demonstrating remarkable tumor homing potential with the tumor growth inhibition rate of 97.2 %. These findings indicated the significant promise of HA-IM-SLNs@CUR in the realm of cancer drug delivery.

Asunto(s)

Antineoplásicos , Curcumina , Endosomas , Nanopartículas , Tamaño de la Partícula , Curcumina/farmacología , Curcumina/química , Humanos , Nanopartículas/química , Animales , Endosomas/metabolismo , Endosomas/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/administración & dosificación , Células Hep G2 , Liberación de Fármacos , Ratones , Lípidos/química , Sistemas de Liberación de Medicamentos , Proliferación Celular/efectos de los fármacos , Hígado/metabolismo , Hígado/efectos de los fármacos , Propiedades de Superficie , Portadores de Fármacos/química , Ácidos Esteáricos/química , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Imidazoles/química , Imidazoles/farmacología , Ratones Desnudos , Ácido Hialurónico/química , Ratones Endogámicos BALB C , Liposomas

RESUMEN

The synthesis and characterization of nine Schiff bases of pyrazolone ligands HLn (n = 1-9) and the corresponding zinc(II) complexes 1-9 of composition [Zn(Ln)2] (n = 1-9) are reported. The molecular structures of complexes 2, 3, 4, 8, and 9 were determined by single-crystal X-ray diffraction analysis, highlighting in all cases a distorted tetrahedral geometry around the Zn(II) ion. Density functional theory studies are performed on both the HLn ligands and the derived complexes. A mechanism of dissociation and hydrolyzation of the coordinated Schiff base ligands is suggested, confirmed experimentally by powder X-ray diffraction study and photophysical studies. Complexes 1-9 were investigated in vitro as anticancer agents, along with mutant p53 (mutp53) protein levels in human cancer cell lines carrying R175H and R273H mutp53 proteins. Only those complexes with the highest Zn(II) ion release via dissociation have shown a significant cytotoxic activity with reduction of mutp53 protein levels.

Asunto(s)

Antineoplásicos , Complejos de Coordinación , Pirazolonas , Proteína p53 Supresora de Tumor , Zinc , Humanos , Pirazolonas/farmacología , Pirazolonas/química , Pirazolonas/síntesis química , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Zinc/química , Zinc/farmacología , Zinc/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Línea Celular Tumoral , Mutación , Bases de Schiff/química , Bases de Schiff/farmacología , Bases de Schiff/síntesis química , Relación Estructura-Actividad , Ensayos de Selección de Medicamentos Antitumorales , Modelos Moleculares , Cristalografía por Rayos X