RESUMEN
The dominant role of non-homologous end-joining in the repair of radiation-induced double-strand breaks identifies DNA-dependent protein kinase (DNA-PK) as an excellent target for the development of radiosensitizers. We report the discovery of a new class of imidazo[4,5-c]pyridine-2-one DNA-PK inhibitors. Structure-activity studies culminated in the identification of 78 as a nM DNA-PK inhibitor with excellent selectivity for DNA-PK compared to related phosphoinositide 3-kinase (PI3K) and PI3K-like kinase (PIKK) families and the broader kinome, and displayed DNA-PK-dependent radiosensitization of HAP1 cells. Compound 78 demonstrated robust radiosensitization of a broad range of cancer cells in vitro, displayed high oral bioavailability, and sensitized colorectal carcinoma (HCT116/54C) and head and neck squamous cell carcinoma (UT-SCC-74B) tumor xenografts to radiation. Compound 78 also provided substantial tumor growth inhibition of HCT116/54C tumor xenografts in combination with radiation. Compound 78 represents a new, potent, and selective class of DNA-PK inhibitors with significant potential as radiosensitizers for cancer treatment.
Asunto(s)
Proteína Quinasa Activada por ADN , Inhibidores de Proteínas Quinasas , Fármacos Sensibilizantes a Radiaciones , Humanos , Proteína Quinasa Activada por ADN/antagonistas & inhibidores , Proteína Quinasa Activada por ADN/metabolismo , Animales , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/síntesis química , Fármacos Sensibilizantes a Radiaciones/farmacología , Fármacos Sensibilizantes a Radiaciones/química , Fármacos Sensibilizantes a Radiaciones/farmacocinética , Fármacos Sensibilizantes a Radiaciones/síntesis química , Relación Estructura-Actividad , Ratones , Línea Celular Tumoral , Imidazoles/farmacología , Imidazoles/química , Imidazoles/síntesis química , Imidazoles/farmacocinética , Piridonas/farmacología , Piridonas/química , Piridonas/síntesis química , Piridonas/farmacocinética , Ensayos Antitumor por Modelo de Xenoinjerto , Ratones Desnudos , RatasRESUMEN
Aim: New quinazoline benzenesulfonamide hybrids 4a-n were synthesized to determine their cytotoxicity and effect on the miR-34a/MDM4/p53 apoptotic pathway. Materials & methods: Cytotoxicity against hepatic, breast, lung and colon cancer cell lines was estimated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Results: Compound 4d was the most potent against HepG2 and MCF-7 cancer cells, with potential apoptotic activity verified by a significant upregulation of miR-34a and p53 gene expressions. The apoptotic effect of 4d was further investigated and showed downregulation of miR-21, VEGF, STAT3 and MDM4 gene expression. Conclusion: The anticancer and apoptotic activities of 4d were enhanced post irradiation by a single dose of 8 Gy γ-radiation. Docking analysis demonstrated a valuable affinity of 4d toward VEGFR2 and MDM4 active sites.
[Box: see text].
Asunto(s)
Antineoplásicos , Apoptosis , MicroARNs , Proteínas Proto-Oncogénicas , Quinazolinas , Fármacos Sensibilizantes a Radiaciones , Sulfonamidas , Proteína p53 Supresora de Tumor , Humanos , MicroARNs/metabolismo , MicroARNs/genética , MicroARNs/antagonistas & inhibidores , Apoptosis/efectos de los fármacos , Proteína p53 Supresora de Tumor/metabolismo , Sulfonamidas/farmacología , Sulfonamidas/química , Sulfonamidas/síntesis química , Quinazolinas/farmacología , Quinazolinas/química , Quinazolinas/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Fármacos Sensibilizantes a Radiaciones/farmacología , Fármacos Sensibilizantes a Radiaciones/química , Fármacos Sensibilizantes a Radiaciones/síntesis química , Simulación del Acoplamiento Molecular , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Estructura Molecular , Línea Celular Tumoral , Proteínas de Ciclo CelularRESUMEN
We report the synthesis of biocompatible perfluorinated micelles designed to improve radiotherapeutic efficacy in a radioresistant tumor environment. In vitro and in vivo behaviors of perfluorinated micelles were assessed at both cellular and tissular levels. The micellar platform offers key advantages as theranostic tool: (i) small size, allowing deep tissue penetration; (ii) oxygen transport to hypoxic tissues; (iii) negligible toxicity in the absence of ionizing radiation; (iv) internalization into cancer cells; (v) potent radiosensitizing effect; and (vi) excellent tumor-targeting properties, as monitored by positron emission tomography. We have demonstrated strong in vitro radiosensitizing effects of the micelle and in vivo tumor targeting, making this nanometric carrier a promising tool for the potentiation of focused radiotherapy.
Asunto(s)
Micelas , Tomografía de Emisión de Positrones , Fármacos Sensibilizantes a Radiaciones , Nanomedicina Teranóstica , Animales , Humanos , Fármacos Sensibilizantes a Radiaciones/química , Fármacos Sensibilizantes a Radiaciones/farmacología , Fármacos Sensibilizantes a Radiaciones/síntesis química , Ratones , Línea Celular Tumoral , Fluorocarburos/química , Fluorocarburos/farmacología , Neoplasias/diagnóstico por imagen , Neoplasias/tratamiento farmacológico , Neoplasias/patologíaRESUMEN
The particular characteristics of hypoxia, immune suppression in the tumor microenvironment, and the lack of accurate imaging guidance lead to the limited effects of stereotactic body radiotherapy (SBRT) in reducing the recurrence rate and mortality of hepatocellular carcinoma (HCC). This research developed a novel theranostic agent based on Bi/Se nanoparticles (NPs), synthesized by a simple reduction reaction method for in vivo CT image-guided SBRT sensitization in mice. After loading Lenvatinib (Len), the obtained Bi/Se-Len NPs had excellent performance in reversing hypoxia and the immune suppression status of HCC. In vivo CT imaging results uncovered that the radiotherapy (RT) area could be accurately labeled after the injection of Bi/Se-Len NPs. Under Len's unique and robust properties, in vivo treatment was then carried out upon injection of Bi/Se-Len NPs, achieving excellent RT sensitization effects in a mouse HCC model. Comprehensive tests and histological stains revealed that Bi/Se-Len NPs could reshape and normalize tumor blood vessels, reduce the hypoxic situation of the tumor, and upregulate tumor-infiltrating CD4+ and CD8+ T lymphocytes around the tumors. Our work highlights an excellent proposal of Bi/Se-Len NPs as theranostic nanoparticles for image-guided HCC radiotherapy.
Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Medios de Contraste/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Nanopartículas del Metal/uso terapéutico , Microambiente Tumoral/efectos de los fármacos , Animales , Bismuto/química , Bismuto/uso terapéutico , Bismuto/toxicidad , Vasos Sanguíneos/efectos de los fármacos , Carcinoma Hepatocelular/diagnóstico por imagen , Línea Celular Tumoral , Medios de Contraste/síntesis química , Medios de Contraste/toxicidad , Portadores de Fármacos/síntesis química , Portadores de Fármacos/uso terapéutico , Portadores de Fármacos/toxicidad , Femenino , Humanos , Hipoxia/tratamiento farmacológico , Neoplasias Hepáticas/diagnóstico por imagen , Linfocitos/efectos de los fármacos , Nanopartículas del Metal/química , Nanopartículas del Metal/toxicidad , Ratones Endogámicos BALB C , Compuestos de Fenilurea/uso terapéutico , Medicina de Precisión , Puntos Cuánticos/química , Puntos Cuánticos/uso terapéutico , Puntos Cuánticos/toxicidad , Quinolinas/uso terapéutico , Fármacos Sensibilizantes a Radiaciones/síntesis química , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Fármacos Sensibilizantes a Radiaciones/toxicidad , Radiocirugia , Selenio/química , Selenio/uso terapéutico , Selenio/toxicidad , Tomografía Computarizada por Rayos XRESUMEN
Twenty new quinazolinone derivatives bearing a piperonyl moiety were designed and synthesized. The structures of the target compounds were in agreement with the microanalytical and spectral data. Compounds 4-10, 13, 14 and 17-27 were screened for their cytotoxic activity against HepG-2 and MCF-7 cancer cell lines. The target compounds showed IC50 in the range of 2.46-36.85 µM and 3.87-88.93 µM for HepG-2 and MCF-7, respectively. The promising compounds 7, 19, 26 and 27 were selected to measure their EGFR inhibitory activity. The IC50 values of the promising compounds were in the range of 146.9-1032.7 nM for EGFR in reference to Erlotinib (IC50 = 96.6 nM). In further studies on compounds 7, 19, 26 and 27 using HepG-2 cell line, there was significant overexpression of p21 and downregulation of two members of IAPs protein family; Survivin and XIAP, relative to their controls. Annexin V-FITC and caspase-3 analyses have established a significant increase in early apoptosis. Moreover, the four selected compounds have impaired cell proliferation by cell cycle arrest at the G2/M phase compared to their respective control. Considering radiotherapy as the primary treatment for many types of solid tumors, the radiosensitizing abilities of compounds 7, 19, 26 and 27 were measured against HepG-2 and MCF-7 cell lines combined with a single dose of 8 Gy gamma radiation. Measurement of the IC50 of the promising compounds after irradiation revealed their ability to sensitize the cells to the lethal effect of gamma irradiation (IC50 = 1.56-4.32 µM and 3.06-5.93 µM for HepG-2 and MCF-7 cells, respectively). Molecular docking was performed to gain insights into the ligand-binding interactions of 7, 19, 26 and 27 inside the EGFR binding sites and revealed their essential interactions, explaining their good activity towards EGFR.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Quinazolinonas/farmacología , Fármacos Sensibilizantes a Radiaciones/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Receptores ErbB/metabolismo , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Quinazolinonas/síntesis química , Quinazolinonas/metabolismo , Fármacos Sensibilizantes a Radiaciones/síntesis química , Fármacos Sensibilizantes a Radiaciones/metabolismo , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/metabolismo , Sulfonamidas/farmacología , Survivin/antagonistas & inhibidores , Proteína Inhibidora de la Apoptosis Ligada a X/antagonistas & inhibidoresRESUMEN
While investigating the possible synergistic effect of the conventional anticancer therapies, which, taken individually, are often ineffective against critical tumors, such as central nervous system (CNS) ones, the design of a theranostic nanovector able to carry and deliver chemotherapy drugs and magnetic hyperthermic agents to the target radiosensitizers (oxygen) was pursued. Alongside the original formulation of polymeric biodegradable oxygen-loaded nanostructures, their properties were fine-tuned to optimize their ability to conjugate therapeutic doses of drugs (doxorubicin) or antitumoral natural substances (curcumin). Oxygen-loaded nanostructures (diameter = 251 ± 13 nm, ζ potential = -29 ± 5 mV) were finally decorated with superparamagnetic iron oxide nanoparticles (SPIONs, diameter = 18 ± 3 nm, ζ potential = 14 ± 4 mV), producing stable, effective and non-agglomerating magnetic nanovectors (diameter = 279 ± 17 nm, ζ potential = -18 ± 7 mV), which could potentially target the tumoral tissues under magnetic driving and are monitorable either by US or MRI imaging.
Asunto(s)
Antibióticos Antineoplásicos/farmacología , Quitosano/química , Hipertermia Inducida/métodos , Nanopartículas de Magnetita/química , Fármacos Sensibilizantes a Radiaciones/farmacología , Nanomedicina Teranóstica/métodos , Antibióticos Antineoplásicos/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Medios de Contraste/síntesis química , Medios de Contraste/farmacología , Curcumina/química , Curcumina/farmacología , Sulfato de Dextran/química , Doxorrubicina/química , Doxorrubicina/farmacología , Composición de Medicamentos/métodos , Humanos , Cinética , Nanopartículas de Magnetita/ultraestructura , Oxígeno/química , Oxígeno/farmacología , Fármacos Sensibilizantes a Radiaciones/síntesis químicaRESUMEN
Novel and effective radiosensitizers that can enhance radiosensitivity of tumor tissues and increase the local radiation dose are highly desirable. In this work, templated by bovine serum albumin (BSA), Bi2Se3-MnO2 nanocomposites (Bi2Se3-MnO2@BSA) were fabricated via biomineralization, while Bi2Se3 nanodots act as radiosensitizers to increase the local radiation dosage because of their strong X-ray attenuation ability, and MnO2 with catalase-like activity can increase the oxygen concentration in tumors by triggering the decomposition of tumor endogenous H2O2 so as to improve the hypoxia-associated radioresistance of tumors. Owing to the interaction of the two components in the interface, Bi2Se3-MnO2@BSA showed promoted catalytic activity compared to MnO2@BSA, favoring tumor radiotherapy (RT) sensitization. BSA templating enabled the nanocomposites with high colloidal stability and biocompatibility as well as satisfactory tumor targeting both in vitro and in vivo; thus, an enhanced RT efficacy was obtained. Moreover, the proposed Bi2Se3-MnO2@BSA exhibited excellent performances in computerized tomography and magnetic resonance imaging. Thus, this work provides a tumor microenvironment-responsive multifunctional theranostic nanoagent with an improved performance for imaging-guided tumor RT sensitization.
Asunto(s)
Antineoplásicos/uso terapéutico , Bismuto/uso terapéutico , Compuestos de Manganeso/uso terapéutico , Nanocompuestos/uso terapéutico , Neoplasias/tratamiento farmacológico , Óxidos/uso terapéutico , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Compuestos de Selenio/uso terapéutico , Animales , Antineoplásicos/síntesis química , Antineoplásicos/efectos de la radiación , Bismuto/química , Catálisis/efectos de la radiación , Bovinos , Línea Celular Tumoral , Medios de Contraste/síntesis química , Medios de Contraste/efectos de la radiación , Medios de Contraste/uso terapéutico , Femenino , Células Endoteliales de la Vena Umbilical Humana , Humanos , Peróxido de Hidrógeno/química , Peróxido de Hidrógeno/metabolismo , Compuestos de Manganeso/química , Compuestos de Manganeso/efectos de la radiación , Ratones Endogámicos BALB C , Nanocompuestos/química , Nanocompuestos/efectos de la radiación , Neoplasias/diagnóstico por imagen , Óxidos/química , Óxidos/efectos de la radiación , Oxígeno/metabolismo , Medicina de Precisión , Fármacos Sensibilizantes a Radiaciones/síntesis química , Fármacos Sensibilizantes a Radiaciones/efectos de la radiación , Compuestos de Selenio/química , Compuestos de Selenio/efectos de la radiaciónRESUMEN
Due to conventional photodynamic therapy encountering serious problems of phototoxicity and low tissue-penetrating depth of light, other dynamic therapy-based therapeutic methods such as sonodynamic therapy (SDT) are expected to be developed. To improve the therapeutic response to SDT, more effective sonosensitizers are imperative. In this study, a novel water-soluble iridium(III)-porphyrin sonosensitizer (IrTMPPS) was synthesized and used for SDT. IrTMPPS generated ample singlet oxygen (1O2) under US irradiation and especially showed distinguished US-activatable abilities at more than 10 cm deep-tissue depths. Interestingly, under US irradiation, IrTMPPS sonocatalytically oxidized intracellular NADH, which would enhance SDT efficiency by breaking the redox balance in the tumor. Moreover, IrTMPPS displayed great sonocytotoxicity toward various cancer cells, and in vivo experiments demonstrated efficient tumor inhibition and anti-metastasis to the lungs in the presence of IrTMPPS and US irradiation. This report gives a novel idea of metal-based sonosensitizers for sonotherapy by fully taking advantage of non-invasiveness, water solubility, and deep tumor therapy.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Porfirinas/uso terapéutico , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Animales , Antineoplásicos/síntesis química , Antineoplásicos/toxicidad , Línea Celular Tumoral , Iridio/química , Iridio/uso terapéutico , Iridio/toxicidad , Ratones , NAD/química , NAD/metabolismo , Neoplasias/patología , Oxidación-Reducción , Porfirinas/síntesis química , Porfirinas/toxicidad , Fármacos Sensibilizantes a Radiaciones/síntesis química , Fármacos Sensibilizantes a Radiaciones/toxicidad , Oxígeno Singlete/metabolismo , Ondas Ultrasónicas , Pez CebraRESUMEN
Correction for 'The potential role of borophene as a radiosensitizer in boron neutron capture therapy (BNCT) and particle therapy (PT)' by Pengyuan Qi et al., Biomater. Sci., 2020, 8, 2778-2785, DOI: .
Asunto(s)
Compuestos de Boro/farmacología , Terapia por Captura de Neutrón de Boro , Carbono/farmacología , Protones , Fármacos Sensibilizantes a Radiaciones/farmacología , Compuestos de Boro/síntesis química , Compuestos de Boro/química , Carbono/química , Muerte Celular/efectos de los fármacos , Membrana Celular/efectos de los fármacos , Humanos , Método de Montecarlo , Nanoestructuras/química , Fármacos Sensibilizantes a Radiaciones/síntesis química , Fármacos Sensibilizantes a Radiaciones/químicaRESUMEN
Reaction between bromo tricarbonyl manganese(I) and N,N'-bis(phenyl)-1,4-diaza-1,3-butadiene ligands, bearing different electron-donating and electron-withdrawing groups R = OCH3, Cl, and NO2 in the ortho- and para-positions on the phenyl substituent, afforded [MnBr(CO)3(N-N)] complexes. The influence of the character and position of the substituent on the dark stability and carbon monoxide releasing kinetics was systematically investigated and correlated with the data of the time-dependent density functional theory calculations. The combined UV/Vis and IR data clearly revealed that the aerated solutions of [MnBr(CO)3(N-N)] in either coordinating or noncoordinating solvents are dark stable and the fluctuations observed during the incubation period especially in the case of the nitro derivatives may be attributed to the exchange of the axial bromo ligand with the coordinating solvent molecules. The free ligands and nitro complexes were non-cytotoxic to HepG2 cells under both the dark and illumination conditions. In the dark, Mn(I) compounds, incorporating o-OCH3 and o-Cl, exhibited excellent cytotoxicity with IC50 values of 18.1 and 11.8 µM, while their para-substituted analogues were inactive in the dark and active upon the irradiation at 365 nm with IC50 values of 5.7 and 6.7 µM, respectively.
Asunto(s)
Antineoplásicos/farmacología , Complejos de Coordinación/farmacología , Fármacos Sensibilizantes a Radiaciones/farmacología , Bases de Schiff/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/efectos de la radiación , Monóxido de Carbono/metabolismo , Supervivencia Celular/efectos de los fármacos , Complejos de Coordinación/síntesis química , Complejos de Coordinación/efectos de la radiación , Teoría Funcional de la Densidad , Ensayos de Selección de Medicamentos Antitumorales , Células Hep G2 , Humanos , Ligandos , Manganeso/química , Modelos Químicos , Fotólisis , Fármacos Sensibilizantes a Radiaciones/síntesis química , Fármacos Sensibilizantes a Radiaciones/efectos de la radiación , Bases de Schiff/síntesis química , Bases de Schiff/efectos de la radiación , Rayos UltravioletaRESUMEN
PURPOSE: The excellent contrast of high atomic number (Z) elements compared to soft tissues has advanced their use as contrast agents for computed tomographic imaging and as potential radiation sensitizers. We evaluated whether gadolinium (Gd) could serve as such a theranostic agent for high-resolution magnetic resonance imaging (MRI) due to its paramagnetic properties and radiosensitization due to its high Z. MATERIALS AND METHODS: To improve the relaxivity of Gd, we coupled it to [60]fullerene, an elemental carbon allotropic nanoparticle that seamlessly traverses physiological barriers . By adding serinol, an aliphatic alcohol derived from amino acid serine, we turned [60]fullerene, which is otherwise insoluble in water, into a highly water-soluble derivative and decorated it externally with a payload of chelated gadolinium ions. RESULTS: When [60]fullerene was functionalized in this manner with two gadolinium ions (Gd2C60), it displayed considerably higher T1 relaxivity at 4.7 T than the commercially used MRI contrast agent, Magnevist, (18.2 mM-1s-1 vs. 4.7 mM-1s-1). Attempts to increase this even further via decoration of [60]fullerene with 12 gadolinium ions was unsuccessful due to a poor water solubility. However, the current formulation of Gd2C60 did not result in any appreciable radiosensitization. CONCLUSION: Our results show a successful generation of a novel contrast agent via decoration of fullerene with two chelated Gd ions. Though this formulation was not successful in generating radiosensitization, other chemical modifications can be further explored to increase radiosensitization potential.
Asunto(s)
Fulerenos/química , Fulerenos/farmacología , Gadolinio/química , Imagen Molecular/métodos , Fármacos Sensibilizantes a Radiaciones/síntesis química , Fármacos Sensibilizantes a Radiaciones/farmacología , Línea Celular Tumoral , Técnicas de Química Sintética , Humanos , Fármacos Sensibilizantes a Radiaciones/química , SolubilidadRESUMEN
BACKGROUND/AIM: Improvement of the efficacy of radiotherapy for lung cancer and glioblastoma is urgently needed. MATERIALS AND METHODS: We synthesized several novel DNA methyltransferase inhibitors and evaluated their potentials as possible radiosensitizers. Eleven non-nucleoside compounds were synthesized and evaluated along with one known compound using human lung cancer (A549) and glioblastoma (U373MG) cells. Cytotoxicity and radiosensitizing effects were evaluated using clonogenic assay. Sensitizer enhancement ratios at a survival fraction of 0.5 were calculated, and statistical analysis was performed using the ratio paired t-test. The inhibitory effects of three selected compounds on the activity of DNA methyltransferase 1 (DNMT1) and the pharmacokinetic profiles were analyzed. RESULTS: All twelve compounds demonstrated various levels of cytotoxicity. Of the twelve compounds, eleven and eight compounds radiosensitized A549 and U373MG cells, respectively, with at least marginal significance (p<0.10). The sensitizer enhancement ratios in A549 and U373MG ranged 1.166-2.537 and 1.083-1.743 among compounds with radiosensitizing effects, respectively. The three selected compounds inhibited DNMT1 activity by 26.5-78.5%. Elimination half-lives ranged from 0.3 to 1.3 h. CONCLUSION: Novel DNA methyltransferase inhibitors with significant radiosensitizing capacity and improved biostability were synthesized. These materials will serve as a basis for the development of novel radiosensitizers.
Asunto(s)
Neoplasias Encefálicas/enzimología , ADN (Citosina-5-)-Metiltransferasa 1/metabolismo , Inhibidores Enzimáticos/farmacología , Glioblastoma/enzimología , Neoplasias Pulmonares/enzimología , Fármacos Sensibilizantes a Radiaciones/farmacología , Células A549 , Neoplasias Encefálicas/terapia , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/efectos de la radiación , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Quimioradioterapia , ADN (Citosina-5-)-Metiltransferasa 1/antagonistas & inhibidores , Regulación hacia Abajo , Inhibidores Enzimáticos/síntesis química , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de la radiación , Glioblastoma/terapia , Humanos , Neoplasias Pulmonares/terapia , Estructura Molecular , Fármacos Sensibilizantes a Radiaciones/síntesis químicaRESUMEN
The integration of multiple therapeutic and diagnostic functions into a single nanoplatform for image-guided cancer therapy has been an emerging trend in nanomedicine. We show here that multifunctional theranostic nanostructures consisting of superparamagnetic iron oxide (SPIO) and gold nanoparticles (AuNPs) scaffolded within graphene oxide nanoflakes (GO-SPIO-Au NFs) can be used for dual photo/radiotherapy by virtue of the near-infrared (NIR) absorbance of GO for photothermal therapy (PTT) and the Z element radiosensitization of AuNPs for enhanced radiation therapy (RT). At the same time, this nanoplatform can also be detected by magnetic resonance (MR) imaging because of the presence of SPIO NPs. Using a mouse carcinoma model, GO-SPIO-Au NF-mediated combined PTT/RT exhibited a 1.85-fold and 1.44-fold higher therapeutic efficacy compared to either NF-mediated PTT or RT alone, respectively, resulting in a complete eradication of tumors. As a sensitive multifunctional theranostic platform, GO-SPIO-Au NFs appear to be a promising nanomaterial for enhanced cancer imaging and therapy.
Asunto(s)
Antineoplásicos/farmacología , Materiales Biocompatibles/farmacología , Carcinoma/tratamiento farmacológico , Imagen por Resonancia Magnética , Fototerapia , Fármacos Sensibilizantes a Radiaciones/farmacología , Nanomedicina Teranóstica , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Materiales Biocompatibles/síntesis química , Materiales Biocompatibles/química , Carcinoma/metabolismo , Carcinoma/patología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Compuestos Férricos/química , Compuestos Férricos/farmacología , Oro/química , Oro/farmacología , Grafito/química , Grafito/farmacología , Masculino , Ensayo de Materiales , Ratones , Ratones Endogámicos BALB C , Nanopartículas/química , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Tamaño de la Partícula , Fármacos Sensibilizantes a Radiaciones/síntesis química , Fármacos Sensibilizantes a Radiaciones/química , Especies Reactivas de Oxígeno/metabolismoRESUMEN
A set of quinazolinones synthesized by the aid of L-norephedrine was assembled to generate novel analogues as potential anticancer and radiosensitizing agents. The new compounds were evaluated for their cytotoxic activity against MDA-MB-231, MCF-7, HepG-2, HCT-116 cancer cell lines and EGFR inhibitory activity. The most active compounds 5 and 6 were screened against MCF-10A normal cell line and displayed lower toxic effects. They proved their relative safety with high selectivity towards MDA-MB-231 breast cancer cell line. Measurement of the radiosensitizing activity for 5 and 6 revealed that they could sensitize the tumour cells after being exposed to a single dose of 8 Gy gamma radiation. Compound 5 was able to induce apoptosis and arrest the cell cycle at the G2-M phase. Molecular docking of 5 and 6 in the active site of EGFR was performed to gain insight into the binding interactions with the key amino acids.
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Inhibidores Enzimáticos/síntesis química , Fenilpropanolamina/química , Quinazolinonas/síntesis química , Fármacos Sensibilizantes a Radiaciones/síntesis química , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Sitios de Unión , Línea Celular , Proliferación Celular/efectos de los fármacos , Proliferación Celular/efectos de la radiación , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Células Epiteliales/citología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/efectos de la radiación , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/química , Receptores ErbB/metabolismo , Rayos gamma , Células HCT116 , Células Hep G2 , Humanos , Concentración 50 Inhibidora , Células MCF-7 , Simulación del Acoplamiento Molecular , Fenilpropanolamina/metabolismo , Fenilpropanolamina/farmacología , Unión Proteica , Conformación Proteica en Hélice alfa , Conformación Proteica en Lámina beta , Dominios y Motivos de Interacción de Proteínas , Quinazolinonas/metabolismo , Quinazolinonas/farmacología , Fármacos Sensibilizantes a Radiaciones/metabolismo , Fármacos Sensibilizantes a Radiaciones/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
AIM: Newly synthesized platinum(IV) complexes with ethylenediamine-N,N'-diacetate ligands (EDDA-type) (butyl-Pt and pentyl-Pt) were investigated against two cancer (A549 lung, and HTB 140 melanoma) and one non-cancerous (MRC-5 embryonic lung fibroblast) human cell lines. MATERIALS AND METHODS: The effects of these agents were compared with those of cisplatin after 6-, 24- and 48-h treatment. Sulforhodamine-B (SRB) assay was performed to estimate the cytotoxic effect, while the inhibitory effect on cell proliferation was measured using 5-bromo-2,-deoxyuridine (BrdU) incorporation assay. Cell cycle analysis was performed by flow cytometry. Type of cell death induced by these agents was determined by electrophoretic analysis of DNA, flow cytometry and by western blot analysis of proteins involved in induction of apoptosis. The effects of gamma irradiation, alone and in combination with platinum-based compounds, were examined by clonogenic and SRB assays. RESULTS: All examined platinum-based compounds had inhibitory and antiproliferative effects on A549 cells, but not on HTB140 and MRC-5 cells. Butyl-Pt, pentyl-Pt and cisplatin arrested the cell cycle in the S-phase and induced apoptotic cell death via regulation of expression of B-cell lymphoma 2 (BCL2) and BCL2-associated X (BAX) proteins. Platinum-based compounds increased the sensitivity of A549 cells to gamma irradiation. Butyl-Pt and pentyl-Pt showed better antitumour effects against A549 cells than did cisplatin, by interfering in cell proliferation and the cell cycle, and by triggering apoptosis. CONCLUSION: The effects of gamma irradiation on tumour cells may be amplified by pre-treatment of cells with platinum-based compounds.
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Antineoplásicos/farmacología , Compuestos Organoplatinos/farmacología , Fármacos Sensibilizantes a Radiaciones/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/efectos de la radiación , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Cisplatino/farmacología , Relación Dosis-Respuesta a Droga , Ácido Edético/análogos & derivados , Ácido Edético/química , Rayos gamma , Humanos , Concentración 50 Inhibidora , Compuestos Organoplatinos/síntesis química , Compuestos Organoplatinos/química , Fármacos Sensibilizantes a Radiaciones/síntesis química , Fármacos Sensibilizantes a Radiaciones/químicaRESUMEN
In the present work, we report the design and synthesis of a set of iodinated quinazolinones carrying benzenesulfonamide moiety as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. The target compounds showed promising inhibitory activity against the four examined human (h) CA isoforms; I, II, IX and XII. Compounds 4-18 displayed variable inhibition constants, ranging as follows: 7.6-782.8 nM for hCA I, 34.4-412.1 nM for hCA II, 29.1-2225.3 nM for hCA IX and 8.8-429.4 nM for hCA XII. Compound 9, the most potent against the tumor-specific CA IX/CA XII (KI = 29.1 and 8.8 nM) gives the possibility to evaluate its cytotoxicity and selectivity in vitro against HepG-2, HCT-116 and MCF-7 cancer cell lines. Compound 9 showed significant cytotoxicity against the tumor cell lines (IC50 = 1.78, 1.94 and 3.07 µM, respectively) and relatively lower toxicity against WI38 normal cell line. The radiosensitizing activity of compound 9 was evaluated and displayed an increase in the radiation-induced cell death in cancer cells after receiving a single dose of 8 Gy gamma radiation. Thus, radiation was able to enhance the antiproliferative activity of compound 9. Molecular docking of 9 into the active site of CA IX and XII revealed the key interactions that could explain its potent activity and selectivity towards these isoforms.
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Antineoplásicos/farmacología , Inhibidores de Anhidrasa Carbónica/farmacología , Anhidrasas Carbónicas/metabolismo , Fármacos Sensibilizantes a Radiaciones/farmacología , Sulfonamidas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Inhibidores de Anhidrasa Carbónica/síntesis química , Inhibidores de Anhidrasa Carbónica/química , Muerte Celular/efectos de los fármacos , Línea Celular , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Simulación del Acoplamiento Molecular , Estructura Molecular , Fármacos Sensibilizantes a Radiaciones/síntesis química , Fármacos Sensibilizantes a Radiaciones/química , Relación Estructura-Actividad , Sulfonamidas/química , BencenosulfonamidasRESUMEN
BACKGROUND: Radiotherapy has an ameliorative effect on a wide variety of tumors, but hepatocellular carcinoma (HCC) is insensitive to this treatment. Overactivated mammalian target of rapamycin (mTOR) plays an important part in the resistance of HCC to radiotherapy; thus, mTOR inhibitors have potential as novel radiosensitizers to enhance the efficacy of radiotherapy for HCC. METHODS: A lead compound was found based on pharmacophore modeling and molecular docking, and optimized according to the differences between the ATP-binding pockets of mTOR and PI3K. The radiosensitizing effect of the optimized compound (2a) was confirmed by colony formation assays and DNA double-strand break assays in vitro. The discovery and preclinical characteristics of this compound are described. RESULTS: The key amino acid residues in mTOR were identified, and a precise virtual screening model was constructed. Compound 2a, with a 4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine scaffold, exhibited promising potency against mTOR (mTOR IC50=7.1 nmol/L (nM)) with 126-fold selectivity over PI3Kα. Moreover, 2a significantly enhanced the sensitivity of HCC to radiotherapy in vitro in a dose-dependent manner. CONCLUSION: A new class of selective mTOR inhibitors was developed and their radiosensitization effects were confirmed. This study also provides a basis for developing mTOR-specific inhibitors for use as radiosensitizers for HCC radiotherapy.
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Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/terapia , Pirimidinonas/farmacología , Fármacos Sensibilizantes a Radiaciones/farmacología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Modelos Moleculares , Estructura Molecular , Pirimidinonas/síntesis química , Pirimidinonas/química , Fármacos Sensibilizantes a Radiaciones/síntesis química , Fármacos Sensibilizantes a Radiaciones/química , Relación Estructura-Actividad , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
The potential role of borophene as a radiosensitizer in PT and BNCT was investigated. Our study focused on two aspects: (1) the synthesis and characterization of borophene nanomaterials; and (2) biocompatibility and dose enhancement. To overcome the limitation of vapor-based technology, we successfully deployed the liquid-phase exfoliation (LPE) method to produce borophene targeting for biomedical applications. Bringing together spatial distribution and dose deposition, the in vitro microdosimetry study was carried out in the presence of borophene. A quantitative study of the dose enhancement ratio (DER) was performed with Monte-Carlo simulation. The synthesized borophene showed good biocompatibility with less than 10% cell death at a concentration of up to 0.2 mg ml-1. The uptake of borophene within individual cells penetrated through cell membranes but outside the nucleus. For proton PT, no significant change in the DER is found. For carbon PT, the DER increases by about 5% as the concentration of 10B reaches 1 mg g-1. For BNCT, a DER of more than 2 can be obtained for a concentration as low as 100 µg g-1. This study lays a foundation for utilizing novel borophene-based nanomaterials as radiosensitizers as well as imaging probes in cancer treatment.
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Compuestos de Boro/farmacología , Terapia por Captura de Neutrón de Boro , Carbono/farmacología , Protones , Fármacos Sensibilizantes a Radiaciones/farmacología , Compuestos de Boro/síntesis química , Compuestos de Boro/química , Carbono/química , Muerte Celular/efectos de los fármacos , Membrana Celular/efectos de los fármacos , Humanos , Método de Montecarlo , Nanoestructuras/química , Fármacos Sensibilizantes a Radiaciones/síntesis química , Fármacos Sensibilizantes a Radiaciones/químicaRESUMEN
Tumor hypoxia is known to be one of the vital factors that aggravate tumor resistance to radiation therapy (RT) in which oxygen plays a critical role in tumor destruction. Herein, we synthesize a simple nanoradiosensitizer based on ultrathin BiO2-x nanosheets (NSs) modified with Tween 20 (T-BiO2-x NSs) to overcome the hypoxia-induced radioresistance as well as increase the efficacy of RT. On the one hand, bismuth as a high-Z element can effectively enhance the sensitivity of RT by depositing a higher radiation dose in tumors. The semiconductor property also endows its photocatalytic ability to produce extra reactive oxygen species (ROS) by reaction with the surrounding water. On the other hand, the defect-abundant BiO2-x NSs are also found to decompose the highly expressed hydrogen peroxide (H2O2) at the tumor site into oxygen (O2) for combating hypoxia. Both in vitro and in vivo experiments indicate that the as-prepared T-BiO2-x NSs could effectively inhibit tumor growth with X-ray irradiation. Our work thus provides a simple nanoradiosensitizer with multifunctionalities for increasing the RT efficacy while alleviating tumor hypoxia at the same time.
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Antineoplásicos/uso terapéutico , Bismuto/uso terapéutico , Nanoestructuras/uso terapéutico , Neoplasias/tratamiento farmacológico , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Hipoxia Tumoral/efectos de los fármacos , Animales , Antineoplásicos/síntesis química , Antineoplásicos/efectos de la radiación , Bismuto/química , Catalasa/química , Línea Celular Tumoral , ADN/metabolismo , Células Endoteliales de la Vena Umbilical Humana , Humanos , Peróxido de Hidrógeno/metabolismo , Ratones Endogámicos BALB C , Nanoestructuras/química , Nanoestructuras/efectos de la radiación , Oxígeno/metabolismo , Fármacos Sensibilizantes a Radiaciones/síntesis química , Fármacos Sensibilizantes a Radiaciones/efectos de la radiación , Rayos X , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Hypoxia is known to be a common feature within many types of solid tumors, which is closely related to the limited efficacy of radiotherapy. Meanwhile, due to the non-discriminatory killing effect of both normal and cancer cells during the radiation process, traditional radiosensitizers could bring severe non-negligible side-effects to the whole body. In this work, stable and atomically precise Mn clusters which possess efficient pH-triggered catalytic selective capacity are developed rationally. Mn clusters could efficiently catalyze oxygen production in an acidic tumor microenvironment, while exhibiting strong reducibility and free radical scavenging ability in neutral circumstances. In vivo experiments show that Mn clusters are able to enhance the radiotherapy effect in the mouse model of 4T1 tumors and protect normal tissues from radiation at the same time. Thus, the present work provides a novel dual-functional strategy to enhance radiotherapy-induced tumor treatment by improving tumor oxygenation and protect normal tissues from radiation simultaneously.