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Primary intracranial ependymoma is a challenging tumor to treat despite the availability of multidisciplinary therapeutic modalities, including surgical resection, radiotherapy, and adjuvant chemotherapy. After the completion of initial treatment, when resistant tumor cells recur, salvage therapy needs to be carried out with a more precise strategy. Circulating tumor cells (CTCs) have specifically been detected and validated for patients with primary or recurrent diffused glioma. The CTC drug screening platform can be used to perform a mini-invasive liquid biopsy for potential drug selection. The validation of potential drugs in a patient-derived xenograft (PDX) mouse model based on the same patient can serve as a preclinical testing platform. Here, we present the application of a drug testing model in a six-year-old girl with primary ependymoma on the posterior fossa, type A (EPN-PFA). She suffered from tumor recurrence with intracranial and spinal seeding at 2 years after her first operation and extraneural metastases in the pleura, lung, mediastinum, and distant femoral bone at 4 years after initial treatment. The CTC screening platform results showed that everolimus and entrectinib could be used to decrease CTC viability. The therapeutic efficacy of these two therapeutic agents has also been validated in a PDX mouse model from the same patient, and the results showed that these two therapeutic agents significantly decreased tumor growth. After precise drug screening and the combination of focal radiation on the femoral bone with everolimus chemotherapy, the whole-body bone scan showed significant shrinkage of the metastatic tumor on the right femoral bone. This novel approach can combine liquid biopsy, CTC drug testing platforms, and PDX model validation to achieve precision medicine in rare and challenging tumors with extraneural metastases.
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Colon cancer is a major malignant neoplasm with a low survival rate for late-stage patients. Therefore, the investigation of molecules regulating colon cancer progression and the discovery of novel therapeutic targets is critical. Mitochondria play a vital role in maintaining the homeostasis of cells. Abnormal mitochondrial metabolism alterations and the induction of glycolysis can facilitate tumor growth; therefore, targeting mitochondrial molecules is suggested to be a promising strategy for cancer treatment. In this study, we investigated the role of this largely unknown mitochondrial factor, chromosome 20 open reading frame 7 (C20orf7), in colon cancer progression. Clustered regularly interspaced short palindromic repeats (CRISPR) technology was utilized for C20orf7 depletion, and functional assays were performed to examine the regulation of C20orf7 in colon cancer cells. We demonstrated that C20orf7 facilitates epithelial-mesenchymal transition (EMT)-mediated cell migration and promotes the proliferation of colon cancer. The anti-cancer drug 5-fluorouracil (5FU) was also applied, and C20orf7 was targeted with a combination of 5FU treatment, which could further enhance the anti-cancer effect in the colon cancer cell line and the xenograft mice model. In summary, this study demonstrated, for the first time, that C20orf7 plays a promotional role in cancer tumorigenesis and could be a promising therapeutic target in colon cancer treatment.
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Neoplasias del Colon , Transición Epitelial-Mesenquimal , Humanos , Ratones , Animales , Transición Epitelial-Mesenquimal/genética , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/genética , Movimiento Celular/genética , Mitocondrias , Fluorouracilo/farmacología , Modelos Animales de Enfermedad , Proliferación Celular/genéticaRESUMEN
Bruton tyrosine kinase (BTK) is linked to multiple signalling pathways that regulate cellular survival, activation, and proliferation. A covalent BTK inhibitor has shown favourable outcomes for treating B cell malignant leukaemia. However, covalent inhibitors require a high reactive warhead that may contribute to unexpected toxicity, poor selectivity, or reduced effectiveness in solid tumours. Herein, we report the identification of a novel noncovalent BTK inhibitor. The binding interactions (i.e. interactions from known BTK inhibitors) for the BTK binding site were identified and incorporated into a structure-based virtual screening (SBVS). Top-rank compounds were selected and testing revealed a BTK inhibitor with >50% inhibition at 10 µM concentration. Examining analogues revealed further BTK inhibitors. When tested across solid tumour cell lines, one inhibitor showed favourable inhibitory activity, suggesting its potential for targeting BTK malignant tumours. This inhibitor could serve as a basis for developing an effective BTK inhibitor targeting solid cancers.
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Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Antineoplásicos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Agammaglobulinemia Tirosina Quinasa/metabolismo , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Relación Estructura-ActividadRESUMEN
Glioblastoma multiforme (GBM) is the most malignant brain tumor in the world, only 25% of GBM patients were alive one year after diagnosis. Although Temozolamide combined with radiation therapy more effectively prolonged the survival rate than radiation alone, the overall survival rate is still dismal. Therefore, a new therapeutic strategy is urgently needed. CDK4/6 inhibitors are newly FDA-approved agents to treat HR-positive, HER2-negative advanced, and metastatic breast cancers, and preclinical results showed that CDK4/6 inhibitors significantly reduced cell proliferation and tumor growth. However, several studies have suggested that CDK4/6 inhibitor-induced non-genetic changes caused treatment failure, including autophagy activation. Therefore, this study aimed to combine an autophagy inhibitor, MPT0L145, with abemaciclib to improve therapeutic efficiency. The use of abemaciclib effectively inhibited cell proliferation via suppression of RB phosphorylation and induced autophagy activation in GBM cancer cells. MPT0L145 treatment alone not only blocked autophagy activation, but also induced generation of ROS and DNA damage in a concentration-dependent manner. Importantly, MPT0L145 had a comparable penetration ability to TMZ in our blood brain barrier permeability assay. Combined MPT0L145 with abemaciclib significantly reduced cell proliferation, suppressed RB phosphorylation, and increased ROS production. In conclusion, the data suggested that blocking autophagy by MPT0L145 synergistically sensitized GBM cancer cells to abemaciclib and represents a potential therapeutic strategy for treating GBM in the future.
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As a two-dimensional nanomaterial, bismuth oxybromide (BiOBr) have attracted tremendous interest in the area of visible-light photocatalysis since it can provide the internal electric field (IEF) through z-axis through its unique electronic band structure. However, the insufficient active sites and rapid recombination rate of charged carriers hamper the efficiency of the photocatalysis. To address these two major obstacles, an enticing strategy of constructing heterojunction was established by introducing Bi2O2(OH)(NO3) (BiON) in BiOBr with the same precursor. Through a facile one-pot hydrothermal synthesis, two Sillén-type layered photocatalysts, with intimately constructed ultrathin heterostructure, was synthesized by the co-precipitation method. In this work, the formation of Bismuth-based heterojunction for charge separation is established by the excessive bismuth nitrate, which subsequently participates with the in situ growth of ultrathin hierarchical microspheres. By attenuating the thickness of BiOBr from 20 nm to 8 nm with the aid of BiON, the photogenerated charges could migrate to the active sites through shorter charge diffusion pathway. Also, the BiOBr and BiON act as an active bridge to promote the separation of electron-hole pairs, which also brings out more active sites due to its increased specific surface area. BiON/BiOBr ultrathin hierarchical microspheres exhibited enhanced visible-light photocatalytic activity for decontaminating several types of pollutants. Besides, the activity of as-prepared BiON/BiOBr was further evaluated by inhibiting the growth of kanamycin-resistant bacteria strains. This study presents a novel strategy to incorporate the crystalline bismuth hydrate nitrate into BiOBr to form ultrathin hierarchical microspheres with high surface area for environmental remediation.
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Restauración y Remediación Ambiental , Microesferas , Bismuto/química , Catálisis , Luz , Nitratos/químicaRESUMEN
Giving patients right dosage is an essential concept of precision medicine. Most of nanocarriers lack of flexible drug capacity and structural stability to be customized for specific treatment, resulting in low therapeutic efficacy and unexpected side effects. Thus, a growing need emerges for fast and rigorous approaches to develop nanoparticles with properties of adjustable dosage and controllable particle size. Poly-l-Lysine is known for its enhanced bioadhesivity and pH-triggered structural swelling effect, which is utilized as the main agent to activate the multistage drug releasing. Inspired by natural bio-assembly system, we report a simple method to self-assemble Poly-l-Lysine-based nanoparticles via supramolecular recognitions of cross-linked pyrenes, which provides noncovalent force to flexibly encapsulate Doxorubincin and to construct robust nanostructures. Pyrene-modified polypeptide self-assemblies are able to adjust drug payload from 1: 10 to 2:1 (drug: polypeptide) without changing its uniform nano-spherical morphology. This nanostructure remained the as-made morphology even after experiencing the long-term (~ 10 weeks) storage at room temperature. Also, the nanoparticles displayed multi-step drug release behaviours and exhibited great in vitro and in vivo cytotoxicity towards colon cancer cells. The as-mentioned nanoparticles provide a novel perspective to compensate the clinical needs of specific drug feedings and scalable synthesis with advantages of simple-synthesis, size-adaptivity, and morphology reversibility.
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Neoplasias del Colon/tratamiento farmacológico , Doxorrubicina , Portadores de Fármacos , Nanopartículas , Animales , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/farmacología , Doxorrubicina/química , Doxorrubicina/farmacología , Portadores de Fármacos/química , Portadores de Fármacos/farmacología , Células HCT116 , Humanos , Concentración de Iones de Hidrógeno , Sustancias Intercalantes/química , Sustancias Intercalantes/farmacología , Ratones , Ratones Desnudos , Nanopartículas/química , Nanopartículas/uso terapéutico , Polilisina/química , Polilisina/farmacología , Pirenos/química , Pirenos/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Scientists have studied intensively the gene delivery carriers for treating genetic diseases. However, there are challenges that impede the application of naked gene-based therapy at the clinical level, such as quick elimination of the circulation, lack of membrane penetrability, and poor endosome trapping. Herein, we develop graphene quantum dots (GQDs)-derivative nanocarriers and introduce polyethylenimine (PEI) to equip the system with enhanced biocompatibility and abundant functional groups for modification. In addition to carrying green fluorescent protein (GFP) as an example of gene delivery, this system covalently binds colon cancer cells targeted antibody and epidermal growth factor receptor (EGFR) to enhance cell membrane penetrability and cell uptake of nanocarriers. To achieve multistrategy cancer therapy, the anticancer drug doxorubicin (Dox) is noncovalently encapsulated to achieve pH-induced drug release at tumor sites and leaves space for further functional gene modification. This nanoparticle serves as a multifunctional gene delivery system, which facilitates improved cytotoxicity and longer-sustained inhibition capacity compared to free Dox treatments in colon cancer cells. Moreover, our GQD composites display compatible tumor suppression ability compared with the free Dox treatment group in xenograft mice experiment with significantly less toxicity. This GQD nanoplatform was demonstrated as a multifunctional gene delivery system that could contribute to treating other genetic diseases in the future.
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Inflammatory bowel disease (IBD) is general term for ulcerative colitis and Crohn's disease, which is chronic intestinal and colorectal inflammation caused by microbial infiltration or immunocyte attack. IBD is not curable, and is highly susceptible to develop into colorectal cancer. Finding agents to alleviate these symptoms, as well as any progression of IBD, is a critical effort. This study evaluates the anti-inflammation and anti-tumor activity of 16-hydroxycleroda-3,13-dien-15,16-olide (HCD) in in vivo and in vitro assays. The result of an IBD mouse model induced using intraperitoneal chemical azoxymethane (AOM)/dextran sodium sulfate (DSS) injection showed that intraperitoneal HCD adminstration could ameliorate the inflammatory symptoms of IBD mice. In the in vitro assay, cytotoxic characteristics and retained signaling pathways of HCD treatment were analyzed by MTT assay, cell cycle analysis, and Western blotting. From cell viability determination, the IC50 of HCD in Caco-2 was significantly lower in 2.30 µM at 48 h when compared to 5-fluorouracil (5-FU) (66.79 µM). By cell cycle and Western blotting analysis, the cell death characteristics of HCD treatment in Caco-2 exhibited the involvement of extrinsic and intrinsic pathways in cell death, for which intrinsic apoptosis was predominantly activated via the reduction in growth factor signaling. These potential treatments against colon cancer demonstrate that HCD could provide a promising adjuvant as an alternative medicine in combating colorectal cancer and IBD.
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Apoptosis , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Diterpenos de Tipo Clerodano/uso terapéutico , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Azoximetano , Biomarcadores de Tumor/metabolismo , Células CACO-2 , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Sulfato de Dextran , Diterpenos de Tipo Clerodano/farmacología , Fluorouracilo/farmacología , Fluorouracilo/uso terapéutico , Células HT29 , Humanos , Inflamación/tratamiento farmacológico , Inflamación/patología , Intestinos/patología , Masculino , Ratones Endogámicos C57BLRESUMEN
Colorectal cancer is a leading cause of death in the world. Despite the progress in therapeutic development, there are still challenges in clinical practice. Nanomedicine has emerged as a solution to enhance traditional therapy. Gold nanoparticles (AuNP) have been demonstrated as potential appliance in treating cancers, yet few studies investigated the capacity of biopolymer-conjugated AuNP in colon cancer as well as examined the system in both cancer cell line and animal models. In this study, we designed the AuNP/biopolymer composite therapeutic system with a chemotherapy agent, doxorubicin (DOX). Two composites with different drug load were applied (referred to as AuPPPyA and AuPPPyB). The composites were characterized by UV spectrum, transmission electron microscope (TEM), zeta potential measurement, and cell cycle analysis. Both therapeutic systems exhibited superior cytotoxic effects compared to DOX alone group. Compatible results were also demonstrated in vivo, as tumor inhibition rate were 46.2% in AuPPPyA and 66.4% in AuPPPyB, which were both higher than that of DOX alone (30%). Cell cycle regulation mediated by our composites was also examined in our study. In conclusion, our data demonstrated that AuNP/biopolymer composites are powerful in treating KRAS gene mutated colorectal cancer, and the system could potentially contribute to other clinical refractory diseases in the future.
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Antineoplásicos/farmacología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Neoplasias Colorrectales/patología , Doxorrubicina/química , Oro/química , Nanopartículas del Metal/química , Proteínas Proto-Oncogénicas p21(ras)/genética , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Biopolímeros/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Doxorrubicina/farmacología , Sistemas de Liberación de Medicamentos , Oro/farmacología , Humanos , Ratones Desnudos , Mutación , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Colon cancer is one of the most lethal cancers worldwide even with the significant progress made in screening techniques and therapeutic agents. Genetic mutations in tumors complicated the treatments, and the survival rate remains low for patients at late or metastatic stages. KRAS gene mutation which leads to failure of the EGFR targeted therapies stands for an example of the challenges in clinical sites. Therefore, development of novel agents for colon cancer treatment is in need. Natural and synthetic coumarin derivatives have been suggested with various biological activities with pharmacologic potential including anti-cancer capacity. Here in this study, five coumarin derivatives, include trifluoromethyl-, dimethoxy-, and/or nitro-substitutions at different positions, were synthesized. Their cancer inhibition potential was investigated in various cancer cell lines. Our data demonstrated that one nitro-coumarin derivate, 5,7-Dimethoxy-4-methyl-6-nitro-chromen-2-one, exhibits cytotoxicity specifically towards colon cancer cells under competitive EC50. Our results showed that this compound can effectively suppress colon cancer cells harboring either wild type or mutant KRAS genes, and that it could inhibit short-term proliferation, long term proliferation, and migration capacities of cancer cells. Finally, we demonstrated that this coumarin derivate facilitates cancer cell death through activation of apoptosis pathway. Our results suggest that this coumarin derivate is a promising lead drug worth further investigation and development for future cancer treatment.
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Apoptosis/efectos de los fármacos , Cumarinas/farmacología , Dióxido de Nitrógeno/química , Proteínas Proto-Oncogénicas p21(ras)/genética , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Cumarinas/química , Ensayos de Selección de Medicamentos Antitumorales , Humanos , MutaciónRESUMEN
Carbon nanomaterials, include carbon nanotubes and graphene nanosheets, have drawn an increasing amount of attention because of their potential applications in daily life or in providing novel therapeutic possibilities for treating diseases. However, the overall biocompatibility, the potential toxic effects of carbon nanomaterials toward human cells, and their modulations in cellular mechanism, are not fully understood. Herein, four types of carbon nanomaterials, include long and short carbon nanotubes and graphene nanosheets, at low and high concentrations, were functionalized and dispersed in the biocompatible buffer for assessment. The surface structure, the morphology, and chemical composition of carbon nanomaterials were characterized. Also, biological assays investigating cellular viability, vitality, cell cycle, and apoptotic cell death were applied on cells co-incubated with nanomaterials, to evaluate the biocompatibility of these nanomaterials in human cells. Our data suggested that even though co-incubation of nanomaterials did not seem to affect the viability of cells notably, high concentrations (50 ug/ml) of SW could lead to unhealthy cells, and we observed dramatic G2 arrest effect mediated by p21 induction in high SW incubated cells. Other nanomaterials at high concentration may also alter cell cycle profile of the cells. In summary, our data demonstrated that these nanomaterials could regulate cell cycle and lead to apoptosis at high concentrations, and the underling molecular mechanisms have been addressed. Caution should be taken on their concentration when nanomaterials are in used in future medical applications.
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Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Grafito/química , Nanoestructuras/química , Nanotubos de Carbono/química , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Grafito/farmacología , Humanos , Ensayo de Materiales , Propiedades de SuperficieRESUMEN
Colon cancer is one of the most common cancers in the developed countries. The association between transforming growth factor TGFα and human cancer incidence has been suggested, yet, the regulatory roles of TGFα and the molecular mechanisms remain unknown, especially in colon cancer. We aim to investigate the functional regulations of TGFα in colon cancer progression. Two colon cancer cell lines were applied, and plasmid overexpression and siRNA-mediated depletion techniques were used to verify the role of TGFα in colon cancer. Cell proliferation was analyzed by MTS assay and colony formation assay, and western blot assay was used to examine protein expression. Migration, invasion, and reporter assays were also carried out to study the regulations of TGFα in colon cancer. Our results evidenced that expression of TGFα facilitates short-term and long-term proliferations of colon cancer cells. Moreover, TGFα was suggested as a migration-and-invasion promoting factor of colon cancer. Finally, our data indicated that TGFα modulates epithelial-mesenchymal transition (EMT) markers and NFκB signaling pathway in colon cancer cells. We provide the first time evidence of the promoting role TGFα plays in colon cancer tumorigenesis with proposed regulatory mechanisms involving EMT alteration and NFκB signaling pathway.