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1.
Nat Commun ; 12(1): 1407, 2021 03 03.
Artículo en Inglés | MEDLINE | ID: mdl-33658498

RESUMEN

Malignant rhabdoid tumour (MRT) is an often lethal childhood cancer that, like many paediatric tumours, is thought to arise from aberrant fetal development. The embryonic root and differentiation pathways underpinning MRT are not firmly established. Here, we study the origin of MRT by combining phylogenetic analyses and single-cell mRNA studies in patient-derived organoids. Comparison of somatic mutations shared between cancer and surrounding normal tissues places MRT in a lineage with neural crest-derived Schwann cells. Single-cell mRNA readouts of MRT differentiation, which we examine by reverting the genetic driver mutation underpinning MRT, SMARCB1 loss, suggest that cells are blocked en route to differentiating into mesenchyme. Quantitative transcriptional predictions indicate that combined HDAC and mTOR inhibition mimic MRT differentiation, which we confirm experimentally. Our study defines the developmental block of MRT and reveals potential differentiation therapies.


Asunto(s)
Mutación , Tumor Rabdoide/genética , Tumor Rabdoide/patología , Diferenciación Celular/genética , Metilación de ADN , Ensayos de Selección de Medicamentos Antitumorales , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Cresta Neural/patología , Filogenia , Tumor Rabdoide/tratamiento farmacológico , Proteína SMARCB1/genética , Análisis de la Célula Individual , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Técnicas de Cultivo de Tejidos/métodos
2.
Eur J Med Chem ; 215: 113267, 2021 Apr 05.
Artículo en Inglés | MEDLINE | ID: mdl-33639344

RESUMEN

Inhibitors of the proteasome have been extensively studied for their applications in the treatment of human diseases such as hematologic malignancies, autoimmune disorders, and viral infections. Many of the proteasome inhibitors reported in the literature target the non-primed site of proteasome's substrate binding pocket. In this study, we designed, synthesized and characterized a series of novel α-keto phenylamide derivatives aimed at both the primed and non-primed sites of the proteasome. In these derivatives, different substituted phenyl groups at the head group targeting the primed site were incorporated in order to investigate their structure-activity relationship and optimize the potency of α-keto phenylamides. In addition, the biological effects of modifications at the cap moiety, P1, P2 and P3 side chain positions were explored. Many derivatives displayed highly potent biological activities in proteasome inhibition and anticancer activity against a panel of six cancer cell lines, which were further rationalized by molecular modeling analyses. Furthermore, a representative α-ketoamide derivative was tested and found to be active in inhibiting the cellular infection of SARS-CoV-2 which causes the COVID-19 pandemic. These results demonstrate that this new class of α-ketoamide derivatives are potent anticancer agents and provide experimental evidence of the anti-SARS-CoV-2 effect by one of them, thus suggesting a possible new lead to develop antiviral therapeutics for COVID-19.


Asunto(s)
Amidas/farmacología , Antineoplásicos/farmacología , Antivirales/farmacología , Cetonas/farmacología , Inhibidores de Proteasoma/farmacología , /efectos de los fármacos , Amidas/síntesis química , Amidas/metabolismo , Antineoplásicos/síntesis química , Antineoplásicos/metabolismo , Antivirales/síntesis química , Antivirales/metabolismo , Sitios de Unión , Calpaína/química , Calpaína/metabolismo , Línea Celular Tumoral , /metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Cetonas/síntesis química , Cetonas/metabolismo , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Estructura Molecular , Complejo de la Endopetidasa Proteasomal/química , Complejo de la Endopetidasa Proteasomal/metabolismo , Inhibidores de Proteasoma/síntesis química , Inhibidores de Proteasoma/metabolismo , Unión Proteica , Relación Estructura-Actividad
3.
ACS Appl Mater Interfaces ; 13(5): 6053-6068, 2021 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-33525873

RESUMEN

Nanomedicine developed to date by means of directly encapsulating cytotoxins suffers from crucial drawbacks, including premature release and detoxification prior to arrival at pharmaceutics targets. To these respects, redox-responsive polymeric prodrugs of platinum (Pt) and camptothecin (CPT), selectively and concomitantly activated in the cytoplasm, were elaborated in manufacture of dual prodrug nanomedicine. Herein, multiple CPTs were conjugated to poly(lysine) (PLys) segments of block copolymeric poly(ethylene glycol) (PEG)-PLys through the redox responsive disulfide linkage [PEG-PLys(ss-CPT)] followed by reversible conversion of amino groups from PLys into carboxyl groups based on their reaction with cis-aconitic anhydride [PEG-PLys(ss-CPT&CAA)]. On the other hand, Pt(IV) in conjugation with dendritic polyamindoamine [(G3-PAMAM-Pt(IV)] was synthesized for electrostatic complexation with PEG-PLys(ss-CPT&CAA) into dual prodrug nanomedicine. Subsequent investigations proved that the elaborated nanomedicine could sequentially respond to intracellular chemical potentials to overcome a string of predefined biological barriers and facilitate intracellular trafficking. Notably, PEG-PLys(ss-CPT&CAA) capable of responding to the acidic endosomal microenvironment for transformation into endosome-disruptive PEG-PLys(ss-CPT), as well as release of G3-PAMAM-Pt(IV) from nanomedicine, prompted transclocation of therapeutic payloads from endosomes into cytosols. Moreover, concurrent activation and liberation of cytotoxic CPT and Pt(II) owing to their facile responsiveness to the cytoplasmic reducing microenvironment have demonstrated overwhelming cytotoxic potencies. Eventually, systemic administration of the dual prodrug construct exerted potent tumor suppression efficacy in treatment of intractable solid breast adenocarcinoma, as well as an appreciable safety profile. The present study illustrated the first example of nanomedicine with a dual prodrug motif, precisely and concomitantly activated by the same subcellular stimuli before approaching pharmaceutic action targets, thus shedding important implication in development of advanced nanomedicine to seek maximized pharmaceutic outcomes.


Asunto(s)
Antineoplásicos/farmacología , Camptotecina/farmacología , Citotoxinas/farmacología , Nanomedicina , Compuestos Organoplatinos/farmacología , Profármacos/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Camptotecina/síntesis química , Camptotecina/química , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Citotoxinas/síntesis química , Citotoxinas/química , Liberación de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Concentración de Iones de Hidrógeno , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Endogámicos BALB C , Compuestos Organoplatinos/síntesis química , Compuestos Organoplatinos/química , Tamaño de la Partícula , Profármacos/síntesis química , Profármacos/química , Propiedades de Superficie , Células Tumorales Cultivadas
4.
ACS Appl Mater Interfaces ; 13(6): 7115-7126, 2021 Feb 17.
Artículo en Inglés | MEDLINE | ID: mdl-33543935

RESUMEN

The success of cancer therapy is always accompanied by severe side effects due to the high amount of toxic antitumor drugs that off-target normal organs/tissues. Herein, we report the development of a trifunctional layered double hydroxide (LDH) nanosystem for combined photochemotherapy of skin cancer at very low therapeutic doses. This nanosystem (ICG/Cu-LDH@BSA-DOX) is composed of acid-responsive bovine serum albumin-doxorubicin prodrug (BSA-DOX) and indocyanine green (ICG)-intercalated Cu-doped LDH nanoparticle. ICG/Cu-LDH@BSA-DOX is able to release DOX in an acid-triggered manner, efficiently and simultaneously generates heating and reactive oxygen species (ROS) upon 808 nm laser irradiation, and synergistically induces apoptosis of skin cancer cells. In vivo therapeutic evaluations demonstrate that ICG/Cu-LDH@BSA-DOX nearly eradicated the tumor tissues upon one-course treatment using very low doses of therapeutic agents (0.175 mg/kg DOX, 0.5 mg/kg Cu, and 0.25 mg/kg ICG) upon very mild 808 nm laser irradiation (0.3 W/cm2 for 2 min). This work thus provides a novel strategy to design anticancer nanomedicine for efficient combination cancer treatment with minimal side effects in clinical applications.


Asunto(s)
Antibióticos Antineoplásicos/farmacología , Doxorrubicina/farmacología , Hidróxidos/farmacología , Melanoma/terapia , Fotoquimioterapia , Neoplasias Cutáneas/terapia , Animales , Antibióticos Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cobre/química , Cobre/farmacología , Relación Dosis-Respuesta a Droga , Doxorrubicina/química , Ensayos de Selección de Medicamentos Antitumorales , Hidróxidos/química , Verde de Indocianina/química , Verde de Indocianina/farmacología , Rayos Láser , Melanoma/metabolismo , Melanoma/patología , Ratones , Estructura Molecular , Tamaño de la Partícula , Especies Reactivas de Oxígeno/metabolismo , Albúmina Sérica Bovina/química , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Propiedades de Superficie
5.
ACS Appl Mater Interfaces ; 13(7): 7987-7996, 2021 Feb 24.
Artículo en Inglés | MEDLINE | ID: mdl-33560829

RESUMEN

The development of multifunctional photosensitizers (PSs) with aggregation-induced emission (AIE) properties plays a critical role in promoting the progress of the photodynamic therapy (PDT). In this work, a multifunctional PS (named DSABBT NPs) with AIE activity has been designed and prepared to carry out ultrafast staining, excellent two-photon bioimaging, and high-efficiency image-guided PDT. Simply, DSABBT with AIE characteristic was synthesized by one-step Schiff reaction of 4-(diethylamino)-salicylaldehyde (DSA) and 4,7-bis(4-aminophenyl)-2,1,3-benzothiadiazole (BBT). Then, DSABBT and DSPE-PEG2000-cRGD generate nanoparticles (NPs) easily in an ultrapure water/tetrahydrofuran mixture through a facile nanoprecipitation at room temperature. We found that DSABBT NPs exhibit bright solid-state fluorescence with large stokes shifts (180 nm) and two-photon absorption cross-section (1700 GM). Importantly, DSABBT NPs exhibited excellent ability of ultrafast staining and two-photon imaging, which can readily label suborganelles by subtly shaking the living cells for 5 s under mild conditions. Moreover, DSABBT NPs displayed high singlet oxygen (1O2) generation capacity and remarkable image-guided PDT efficiency. Therefore, DSABBT NPs can act as the promising candidate for multifunctional PSs, which can destroy cancer cells and block malignant tumor growth via the production of reactive oxygen species upon irradiation conditions. These outcomes provide us with a selectable strategy for developing multifunctional theranostic systems.


Asunto(s)
Antineoplásicos/farmacología , Colorantes Fluorescentes/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Microscopía de Fluorescencia por Excitación Multifotónica , Fotoquimioterapia , Fármacos Fotosensibilizantes/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Colorantes Fluorescentes/síntesis química , Colorantes Fluorescentes/química , Humanos , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/patología , Estructura Molecular , Imagen Óptica , Tamaño de la Partícula , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/química , Propiedades de Superficie
6.
ACS Appl Mater Interfaces ; 13(7): 8940-8951, 2021 Feb 24.
Artículo en Inglés | MEDLINE | ID: mdl-33565847

RESUMEN

Chemotherapy is currently the most universal therapeutics to tumor treatment; however, limited curative effect and undesirable drug resistance effect are the two major clinical bottlenecks. Herein, we develop a two-in-one cross-linking strategy to prepare a stimuli-responsive prodrug nanogel by virtue of delivering a combination of chemotherapeutic drugs of 10-hydroxy camptothecin and doxorubicin for ameliorating the deficiencies of chemotherapy and amplifying the cancer therapeutic efficiency. The obtained prodrug nanogel has both high drug loading capacity and suitable nanoscale size, which are beneficial to the cell uptake and tumor penetration. Moreover, the chemotherapeutic drugs are released from the prodrug nanogel in response to the reductive tumor microenvironment, enhancing tumor growth inhibition in vitro and in vivo by the synergistic DNA damage. Based on these results, the unique prodrug nanogel would be a promising candidate for satisfactory tumor treatment-based chemotherapy by a simple but efficient strategy.


Asunto(s)
Antineoplásicos/farmacología , Camptotecina/farmacología , Reactivos de Enlaces Cruzados/farmacología , Doxorrubicina/farmacología , Profármacos/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Camptotecina/química , Cápsulas/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Reactivos de Enlaces Cruzados/síntesis química , Reactivos de Enlaces Cruzados/química , Daño del ADN/efectos de los fármacos , Doxorrubicina/química , Liberación de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Nanogeles/química , Oxidación-Reducción , Tamaño de la Partícula , Polietilenglicoles/química , Polietileneimina/química , Profármacos/síntesis química , Profármacos/química , Propiedades de Superficie , Microambiente Tumoral/efectos de los fármacos
7.
ACS Appl Mater Interfaces ; 13(7): 8060-8070, 2021 Feb 24.
Artículo en Inglés | MEDLINE | ID: mdl-33576220

RESUMEN

The high activity of specific enzymes in cancer has been utilized in cancer diagnosis, as well as tumor-targeted drug delivery. NAD(P)H:quinone oxidoreductase-1 (NQO1), an overexpressed enzyme in certain tumor types, maintains homeostasis and inhibits oxidative stress caused by elevated reactive oxygen species (ROS) in tumor cells. The activity of NQO1 in lung and liver cancer cells is increased compared to that in normal cells. Interestingly, NQO1 reacts with trimethyl-locked quinone propionic acid (QPA) and produces a lactone-based group via intramolecular cyclization. Toward this objective, we synthesized an amphiphilic block copolymer (QPA-P) composed of NQO1 enzyme-triggered depolymerizable QPA-locked polycaprolactone (PCL) and poly(ethylene glycol) (PEG) as hydrophobic and hydrophilic constituents, respectively. This QPA-P formed self-assembled micelles in aqueous conditions. It was observed that NQO1 catalyzed the depolymerization of QPA-locked PCL via a cascade two-step cyclization process, which eventually induced the dissociation of micellar structure and triggered the release of loaded drugs at the target cancer cells. Compared to the control group, the NQO1-responsive micelle showed NQO1-triggered intracellular drug release and enhanced anticancer effects. These results indicate that the NQO1-responsive polymeric micelles present a promising potential for improving therapeutic efficacy of an anticancer drug delivery system.


Asunto(s)
Antibióticos Antineoplásicos/farmacología , Doxorrubicina/farmacología , Sistemas de Liberación de Medicamentos , Neoplasias Pulmonares/tratamiento farmacológico , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , Polímeros/metabolismo , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/metabolismo , Benzoquinonas/química , Benzoquinonas/metabolismo , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ciclización , Doxorrubicina/química , Doxorrubicina/metabolismo , Liberación de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Lactonas/química , Lactonas/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Micelas , Estructura Molecular , NAD(P)H Deshidrogenasa (Quinona)/química , Tamaño de la Partícula , Polimerizacion , Polímeros/química , Propionatos/química , Propionatos/metabolismo , Propiedades de Superficie , Células Tumorales Cultivadas
8.
ACS Appl Mater Interfaces ; 13(7): 8026-8041, 2021 Feb 24.
Artículo en Inglés | MEDLINE | ID: mdl-33577301

RESUMEN

Photodynamic therapy (PDT) is a promising strategy for cancer treatment. It can not only generate reactive oxygen species (ROS) to cause the chemical damage of tumor cells in the presence of enough oxygen but also promote the antitumor immunity of T cells through enhancing the production of interferon γ (IFN-γ). However, one phenomenon is ignored so far that the enhanced production of IFN-γ caused by PDT may significantly increase the expression of programmed death-ligand 1 (PD-L1) on the tumor cell membrane and thus could inhibit the immune killing effects of T cells. Herein, we report the construction of a composite by loading metformin (Met) and IR775 into a clinically usable liposome as a two-in-one nanoplatform (IR775@Met@Lip) to solve this problem. The IR775@Met@Lip could reverse tumor hypoxia to enhance ROS production to elicit more chemical damage. Besides, the overexpression of PD-L1 by PDT was also effectively down-regulated. These therapeutic benefits including decreased PD-L1 expression, alleviated T cell exhaustion, and reversed tumor hypoxia successfully suppressed both the primary and abscopal tumor growth in bladder and colon cancers, respectively. Combining with its excellent biocompatibility, our results indicate that this IR775@Met@Lip system has great potential to become a highly effective cancer therapy modality.


Asunto(s)
Antineoplásicos/farmacología , Antígeno B7-H1/antagonistas & inhibidores , Inmunoterapia , Metformina/farmacología , Fotoquimioterapia , Animales , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Antígeno B7-H1/análisis , Antígeno B7-H1/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Indoles/química , Indoles/farmacología , Liposomas/química , Liposomas/farmacología , Masculino , Metformina/química , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Neoplasias Experimentales/diagnóstico por imagen , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Imagen Óptica , Tamaño de la Partícula , Propiedades de Superficie , Hipoxia Tumoral/efectos de los fármacos
9.
ACS Appl Mater Interfaces ; 13(7): 7977-7986, 2021 Feb 24.
Artículo en Inglés | MEDLINE | ID: mdl-33586952

RESUMEN

Encapsulins, a prokaryotic class of self-assembling protein nanocompartments, are being re-engineered to serve as "nanoreactors" for the augmentation or creation of key biochemical reactions. However, approaches that allow encapsulin nanoreactors to be functionally activated with spatial and temporal precision are lacking. We report the construction of a light-responsive encapsulin nanoreactor for "on demand" production of reactive oxygen species (ROS). Herein, encapsulins were loaded with the fluorescent flavoprotein mini-singlet oxygen generator (miniSOG), a biological photosensitizer that is activated by blue light to generate ROS, primarily singlet oxygen (1O2). We established that the nanocompartments stably encased miniSOG and in response to blue light were able to mediate the photoconversion of molecular oxygen into ROS. Using an in vitro model of lung cancer, we showed that ROS generated by the nanoreactor triggered photosensitized oxidation reactions which exerted a toxic effect on tumor cells, suggesting utility in photodynamic therapy. This encapsulin nanoreactor thus represents a platform for the light-controlled initiation and/or modulation of ROS-driven processes in biomedicine and biotechnology.


Asunto(s)
Antineoplásicos/farmacología , Ingeniería Biomédica , Colorantes Fluorescentes/farmacología , Luz , Neoplasias Pulmonares/tratamiento farmacológico , Fotoquimioterapia , Fármacos Fotosensibilizantes/farmacología , Células A549 , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Flavoproteínas/química , Flavoproteínas/metabolismo , Colorantes Fluorescentes/química , Humanos , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/patología , Nanocompuestos/química , Tamaño de la Partícula , Fármacos Fotosensibilizantes/química , Especies Reactivas de Oxígeno/análisis , Especies Reactivas de Oxígeno/metabolismo , Oxígeno Singlete/análisis , Oxígeno Singlete/metabolismo , Espectrometría de Fluorescencia , Propiedades de Superficie
10.
ACS Appl Mater Interfaces ; 13(7): 7945-7954, 2021 Feb 24.
Artículo en Inglés | MEDLINE | ID: mdl-33588525

RESUMEN

HJS and DHJS, two near-infrared emissive and mitochondria-targeted therapy probes, have been designed. They exhibited photothermal & photodynamic cytotoxicity and aggregation-induced emission (AIE) characteristics. Interestingly, we could receive fluorescence immediately after adding the probes without washing in 1 min. They could quickly enter cancer cells and selectively localized to the mitochondria firstly. When the concentration of probes was low (<5 µM), they could respond sensitively to the mitochondrial membrane potential and would selectively enter the mitochondria with red fluorescence. However, when the concentration was high (≥5 µM), they would preferentially enter the mitochondria and have the property of dual-channel fluorescence imaging (red and near-infrared) even after 24 h. What's more, they increased the intracellular reactive oxygen species (ROS) levels, decreased the mitochondrial membrane potentials, and then induced apoptosis, which were proved by confocal imaging and flow cytometry experiments. In addition, the results of photothermal experiment and cytotoxicity test showed that the probes had good photothermal and photodynamic toxicity to cancer cells. In vitro and in vivo experiments also proved the excellent near-infrared (NIR) imaging ability, good biocompatibility and certain inhibition of tumor growth ability of DHJS.


Asunto(s)
Antineoplásicos/farmacología , Colorantes Fluorescentes/farmacología , Mitocondrias/efectos de los fármacos , Fotoquimioterapia , Neoplasias de la Próstata/tratamiento farmacológico , Animales , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Colorantes Fluorescentes/química , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias Experimentales/diagnóstico por imagen , Neoplasias Experimentales/tratamiento farmacológico , Imagen Óptica , Células PC-3 , Tamaño de la Partícula , Neoplasias de la Próstata/diagnóstico por imagen , Propiedades de Superficie , Células Tumorales Cultivadas
11.
Gene ; 779: 145494, 2021 May 05.
Artículo en Inglés | MEDLINE | ID: mdl-33588036

RESUMEN

Microalgae, one of the most important classes of biomass producers, can produce exopolysaccharides similar to bacteria. The exopolysaccharide from Chlorella (CEPS) displays remarkable anticancer activity the mechanism of which remains to be elucidated. In this study, we analyzed the inhibitory effect of CEPS on the growth of HeLa cells. The results showed that CEPS inhibited the proliferation, decreased the viability, and changed the morphology of HeLa cells. Transcriptome analysis showed that 1894 genes were differentially expressed in the CEPS-treated group compared with the control group, including 1076 genes that were upregulated and 818 genes that were downregulated. The results of gene function enrichment analysis showed that the differentially expressed genes (DEGs) were significantly enriched in apoptosis and tumor-related biological processes and participated in several cancer and apoptosisrelated signaling pathways, including the MAPK signaling pathway, TNF signaling pathway, and the PI3K-Akt signaling pathway. The protein-protein interaction network identified 13 DEGs including PTPN11, RSAD2, ISG15, IFIT1, MX2, IFIT2, OASL, OAS1, JUN, OAS2, XAF1, ISG20, and IRF9 as hub genes. Our results suggest that CEPS is a promising therapeutic drug for the follow-up interventional therapy of cancer.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Chlorella/química , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Polisacáridos/farmacología , Animales , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/química , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Chlorocebus aethiops , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Perfilación de la Expresión Génica/métodos , Células HeLa , Humanos , Fosfatidilinositol 3-Quinasas/genética , Polisacáridos/administración & dosificación , Polisacáridos/química , Mapas de Interacción de Proteínas/efectos de los fármacos , Mapas de Interacción de Proteínas/genética , Células Vero
12.
J Med Chem ; 64(3): 1584-1592, 2021 02 11.
Artículo en Inglés | MEDLINE | ID: mdl-33522809

RESUMEN

Increased activity of the lysine methyltransferase NSD2 driven by translocation and activating mutations is associated with multiple myeloma and acute lymphoblastic leukemia, but no NSD2-targeting chemical probe has been reported to date. Here, we present the first antagonists that block the protein-protein interaction between the N-terminal PWWP domain of NSD2 and H3K36me2. Using virtual screening and experimental validation, we identified the small-molecule antagonist 3f, which binds to the NSD2-PWWP1 domain with a Kd of 3.4 µM and abrogates histone H3K36me2 binding to the PWWP1 domain in cells. This study establishes an alternative approach to targeting NSD2 and provides a small-molecule antagonist that can be further optimized into a chemical probe to better understand the cellular function of this protein.


Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , N-Metiltransferasa de Histona-Lisina/antagonistas & inhibidores , Proteínas Represoras/antagonistas & inhibidores , Simulación por Computador , Cristalografía por Rayos X , Descubrimiento de Drogas/métodos , Evaluación Preclínica de Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , N-Metiltransferasa de Histona-Lisina/efectos de los fármacos , Humanos , Ligandos , Modelos Moleculares , Simulación del Acoplamiento Molecular , Dominios Proteicos , Proteínas Represoras/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas , Relación Estructura-Actividad
13.
J Med Chem ; 64(3): 1524-1544, 2021 02 11.
Artículo en Inglés | MEDLINE | ID: mdl-33529023

RESUMEN

Clinical and preclinical data reveal that RECQL5 protein overexpression in breast cancer was strongly correlated with poor prognosis, survival, and therapeutic resistance. In the current investigation, we report design, synthesis, and specificity of a small molecule, 4a, which can preferentially kill RECQL5-expressing breast cancers but not RECQL5 knockout. Our stringent analysis showed that compound 4a specifically sensitizes RECQL5-expressing cancers, while it did not have any effect on other members of DNA RECQL-helicases. Integrated approaches of organic synthesis, biochemical, in silico molecular simulation, knockouts, functional mutation, and rescue experiments showed that 4a potently inhibits RECQL5-helicase activity and stabilizes RECQL5-RAD51 physical interaction, leading to impaired HRR and preferential killing of RECQL5-expressing breast cancer. Moreover, 4a treatment led to the efficient sensitization of cisplatin-resistant breast cancers but not normal mammary epithelial cells. Pharmacologically, compound 4a was orally effective in reducing the growth of RECQL5-expressing breast tumors (human xenograft) in NUDE-mice with no appreciable toxicity to the vital organs.


Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , RecQ Helicasas/efectos de los fármacos , Administración Oral , Animales , Antineoplásicos/toxicidad , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Cisplatino/farmacología , Simulación por Computador , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Técnicas de Inactivación de Genes , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Modelos Moleculares , RecQ Helicasas/genética , Ensayos Antitumor por Modelo de Xenoinjerto
14.
ACS Appl Mater Interfaces ; 13(5): 6034-6042, 2021 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-33499584

RESUMEN

MicroRNA (miRNA) represents a promising class of therapeutic nucleic acid drugs, while delivery challenges remain that impede the advancement of miRNA therapy, largely because of in vivo instability and low delivery efficiency. Herein, we discover the dual roles of metal-organic framework (MOF) nanoparticles (ZIF-8) as nanocarriers for miRNA delivery and adjuvants for chemodynamic therapy. The miR-34a-m@ZIF-8 complex demonstrated efficient cellular uptake and lysosomal stimuli-responsive miRNA release. Zn2+ triggered the generation of reactive oxygen species, which consequently induced apoptosis of tumor cells. Released miR-34a-m led to a remarkable decrease in expression of Bcl-2 at both mRNA and protein levels and enhanced cancer cell apoptosis. In vivo experiments showed high efficacy of using miR-34a-m@ZIF-8 to suppress tumor growth via synergistic gene/chemodynamic therapy in a mouse model of triple-negative breast cancer. Our work demonstrates MOFs as a promising nanoplatform for efficient synergetic gene/chemodynamic therapy.


Asunto(s)
Adyuvantes Farmacéuticos/farmacología , Antibióticos Antineoplásicos/farmacología , Doxorrubicina/farmacología , Sistemas de Liberación de Medicamentos , Estructuras Metalorgánicas/química , MicroARNs/farmacología , Nanopartículas/química , Adyuvantes Farmacéuticos/química , Animales , Antibióticos Antineoplásicos/química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/química , Portadores de Fármacos/química , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Neoplasias Mamarias Experimentales/diagnóstico por imagen , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/metabolismo , Ratones , MicroARNs/química , Tamaño de la Partícula , Especies Reactivas de Oxígeno/metabolismo , Propiedades de Superficie , Zeolitas/química , Zeolitas/farmacología
15.
ACS Appl Mater Interfaces ; 13(5): 5999-6010, 2021 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-33506682

RESUMEN

Cellular FLIP (cFLIP) is a crucial player of apoptosis-regulated pathways that is frequently overexpressed in solid cancers. To inhibit c-FLIP, pre- and post-transcriptionally, a multifunctional nanoparticle (NP) was created to deliver cFLIP-specific small interfering RNA (siRNA) into cancer cells. Specifically, Vorinostat (Vor)-loaded mesoporous silica nanoparticles (MSN) were conjugated with polyethylenimine-biotin (PB), followed by electrostatically binding with cFLIP siRNA (Vor/siR@MSN-PB). To stabilize and prolong the circulation time of nanoparticles, a bialdehyde-modified poly(ethylene glycol) (PEG) was cross-linked onto the polyethylenimine (PEI) backbone via the formation of the imine linkage (Schiff base) (Vor/siR@MSN-PB-PEG). The Schiff base is highly stable at physiological pH 7.4 but labile under slightly acidic pH conditions. In the acidic tumor microenvironment (TME), the PEG outer layer could be rapidly cleaved, resulting in the switching of the nanoparticle surface charge to positive, which specifically enhances internalization of the NPs to the biotin-positive tumor cells. Our results demonstrated the successful preparation of Vor/siR@MSN-PB-PEG NPs, in which the siRNA was effectively protected in serum and regulated the expression of cFlip, post-transcriptionally. The presence of the PEG layer resulted in high tumor accumulation and high efficacy in tumor inhibition, which was a result of the efficient cFLIP suppression. Furthermore, in the low-dose regimen of Vorinostat-the pre-transcriptional cFLIP suppressor, treatment with Vor/siR@MSN-PB-PEG NPs was found to be safe with the treated mice, indicating a promising combination regimen for cancer therapy.


Asunto(s)
Antineoplásicos/farmacología , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD/antagonistas & inhibidores , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD/genética , Nanopartículas/química , ARN Interferente Pequeño/farmacología , Vorinostat/farmacología , Animales , Antineoplásicos/química , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Concentración de Iones de Hidrógeno , Ratones , Ratones Endogámicos BALB C , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Tamaño de la Partícula , Polietilenglicoles/química , ARN Interferente Pequeño/química , Propiedades de Superficie , Vorinostat/química
16.
Life Sci ; 270: 119113, 2021 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-33508290

RESUMEN

AIMS: This study aimed to design and screen a dual functional fusion peptide that could penetrate the blood-brain barrier and target neuropilin 1 (NRP1) overexpressed in vascular endothelial cells for the anti-angiogenesis of glioma treatment. MAIN METHODS: At the cellular level, the in vitro anti-angiogenic activity of six NRP1 targeting peptides was screened by testing the ability to inhibit the proliferation and tube formation of HUVECs. Then, the in vitro anti-angiogenic activity of two fusion peptides containing different linkers was screened by testing the ability to inhibit HUVECs proliferation, tube formation and migration. The effect of fusion peptide on VEGFR2 related signal pathway was confirmed by Western-blotting. Surface plasmon resonance technology was used to detect the affinity of the fusion peptide to NRP1. The ability of FITC-labeled peptides to penetrate cells was confirmed by cell uptake assay. By establishing an orthotopic glioma model, we evaluated the ability of FITC-labeled peptides to penetrate the blood-brain barrier and their anti-glioma growth activity in vivo. KEY FINDINGS: We found that NRP1 targeting peptide RP7 and linker cysteine were the most suitable key components in the fusion peptide. We also found that the fusion peptide Tat-C-RP7 we constructed had the strongest ability to penetrate the blood-brain barrier and anti-angiogenic activity in vitro and in vivo. SIGNIFICANCE: At present, NRP1 targeting peptide as a drug delivery tool and molecular probe seems to have received more attention. We constructed a fusion peptide Tat-C-RP7 with strong anti-angiogenic activity for the treatment of glioma.


Asunto(s)
Glioma/metabolismo , Neuropilina-1/metabolismo , Péptidos/farmacología , Inhibidores de la Angiogénesis/farmacología , Animales , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/fisiología , Línea Celular Tumoral , China , Sistemas de Liberación de Medicamentos/métodos , Ensayos de Selección de Medicamentos Antitumorales/métodos , Células Endoteliales/metabolismo , Femenino , Glioma/tratamiento farmacológico , Células Endoteliales de la Vena Umbilical Humana , Humanos , Inmunoterapia , Liposomas/uso terapéutico , Ratones Endogámicos BALB C , Ratones Desnudos , Transducción de Señal/fisiología , Factor A de Crecimiento Endotelial Vascular/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo
17.
ACS Appl Mater Interfaces ; 13(7): 7890-7896, 2021 Feb 24.
Artículo en Inglés | MEDLINE | ID: mdl-33513005

RESUMEN

Nanodrug delivery systems are very promising for highly efficient anticancer drug delivery. However, the present nanosystems are commonly located in the cytoplasm and mediate uncontrolled release of drugs into cytosol, while a large number of anticancer drugs function more efficiently inside the nucleus. Here, we constructed a CRISPR-dCas9-guided and telomerase-responsive nanosystem for nuclear targeting and smart release of anticancer drugs. CRISPR-dCas9 technology has been employed to achieve conjugation of mesoporous silica nanoparticles (MSNs) with a high payload of the active anticancer drug, doxorubicin (DOX). A specifically designed wrapping DNA was used as a telomerase-responsive biogate to encapsulate DOX within MSNs. The wrapping DNA is extended in the presence of telomerase, which is highly activated in tumor cells, but not in normal cells. The extended DNA sequence forms a rigid hairpin-like structure and diffuses away from the MSN surface. CRISPR-dCas9 specifically targets telomere-repetitive sequences at the tips of chromosomes, facilitating the precise delivery of the nanosystem to the nucleus, and effective drug release triggered by telomerase that was enriched around telomeric repeats. This study provides a strategy and nanosystem for nuclear-targeted delivery and tumor-specific release of anticancer drugs that will maximize the efficiency of cancer cell destruction.


Asunto(s)
Antibióticos Antineoplásicos/farmacología , Proteína 9 Asociada a CRISPR/química , Doxorrubicina/farmacología , Sistemas de Liberación de Medicamentos , Nanopartículas/química , Telomerasa/química , Antibióticos Antineoplásicos/química , Proteína 9 Asociada a CRISPR/metabolismo , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Doxorrubicina/química , Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Células HeLa , Humanos , Estructura Molecular , Nanopartículas/metabolismo , Imagen Óptica , Tamaño de la Partícula , Porosidad , Propiedades de Superficie , Telomerasa/metabolismo
18.
Chem Biol Interact ; 335: 109367, 2021 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-33412154

RESUMEN

Metastasis is the leading cause of death in retinoblastoma (Rb) patients. Tubeimoside II (TBMS II) is a compound enriched in the Traditional Chinese Medicine (TCM) Tu Bei Mu. It has been shown to induce cytotoxicity of several types of tumors; however, littler is known about its effect on Rb. This study investigated the influence of TBMS II on TGF-ß1-induced metastasis of human retinoblastoma Y-79 and WERI-Rb-1 cells. The data showed that TBMS II significantly inhibited epithelial-mesenchymal transition (EMT), cell adhesion, migration and invasion via reducing TGF-ß1-induced oxidative stress in Rb cells. Further findings revealed that TBMS II exerted its inhibitory effect against TGF-ß1-induced metastatic progression of Rb cells via suppressing redoxosome-dependent EGFR activation including EGFR phosphorylation and oxidation, and the activation of such signaling attenuated TBMS II's effect. Our study reveals that TBMS II impacts on TGF-ß1-induced metastatic progression of Rb cells, and this information may contribute to better understanding the therapeutic potentials of TBMS II on metastatic Rb.


Asunto(s)
Antineoplásicos/farmacología , Metástasis de la Neoplasia/tratamiento farmacológico , Neoplasias de la Retina/tratamiento farmacológico , Retinoblastoma/tratamiento farmacológico , Saponinas/farmacología , Triterpenos/farmacología , Adhesión Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Transición Epitelial-Mesenquimal/efectos de los fármacos , Receptores ErbB/metabolismo , Humanos , Oxidación-Reducción/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Fosforilación/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo
19.
Int J Biol Macromol ; 170: 688-700, 2021 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-33385452

RESUMEN

Requirement for medication from pathogenic human viruses and cancer diseases are urgently considered, while, numerous reports were focused on investigating easily manufactured and excellently effective therapeutic reagents. Herein, CQDs were prepared with size of 2.1 nm from both of carrageenan and pullulan. CQDs nucleated from pullulan showed higher anti-proliferative effects against cancer cells, while, treatment with 100 µg/mL of CQDs colloids originated from pullulan and carrageenan separately resulted in diminishing of cancer cell viability percent to be 42.1 & 58.7%, respectively. Plaque reduction assay was also affirmed that, 2.5 µg/L of both of pullulan and carrageenan based CQDs exhibited viral inhibition with percent of 44.3& 59.5%, respectively. As a conclusion, pullulan showed seniority over carrageenan in nucleation of CQDs with higher anticancer activities. While, estimation of antiviral performance of the prepared CQDs confirmed the priority of carrageenan compared to pullulan in preparation of CQDs as antiviral laborer.


Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Antivirales/química , Antivirales/farmacología , Puntos Cuánticos/química , Puntos Cuánticos/uso terapéutico , Apoptosis/efectos de los fármacos , Carbono/química , Carragenina/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , Glucanos/química , Tecnología Química Verde , Humanos , Microscopía Electrónica de Transmisión , Coronavirus del Síndrome Respiratorio de Oriente Medio/efectos de los fármacos , Puntos Cuánticos/ultraestructura , Ensayo de Placa Viral
20.
J Mater Chem B ; 9(4): 1040-1048, 2021 01 28.
Artículo en Inglés | MEDLINE | ID: mdl-33392615

RESUMEN

Carrier-free nanomedicines without structural modification are attractive for the development of natural small molecules (NSMs) and biomedical applications. Moreover, the combination of NSMs is expected to obtain nanomedicines with high efficacy and low side effects due to their inherent pharmacological activities and health benefits. However, poor water solubility and low bioavailability of NSMs limit their wider biomedical and clinical applications. In this study, we revealed the co-assembly properties of pentacyclic triterpenoids and constructed a series of carrier-free nanodrugs, which are co-assembled nanoparticles (NPs) formed by the combination of two NSMs via a supramolecular assembly strategy. Experimental work and simulation studies were combined to reveal the co-assembly mechanism of non-covalent interactions between NSMs. Not only do co-assembled NPs have rapid cellular uptake ability and passive targeting tumor ability based on the EPR effect, but also their constituent units could arrest the cell cycle at different stages of tumor cells and induce apoptosis, showing synergistic anti-tumor effects (CI < 0.7). Compared with self-assembled NPs and positive control, co-assembled NPs show the strongest therapeutic effect in vivo. Importantly, the co-assembled NPs highlight the unique advantages of NSMs in terms of biosafety and health benefits, and systemic toxicity and histological examination confirm that co-assembled NPs have reliable biosafety, and no side effects and nano toxicity risks were observed.


Asunto(s)
Antineoplásicos/farmacología , Nanopartículas/química , Paclitaxel/farmacología , Triterpenos Pentacíclicos/farmacología , Animales , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Células MCF-7 , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Endogámicos BALB C , Nanomedicina , Imagen Óptica , Paclitaxel/química , Tamaño de la Partícula , Triterpenos Pentacíclicos/química , Propiedades de Superficie , Células Tumorales Cultivadas
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