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1.
Science ; 372(6537)2021 04 02.
Artículo en Inglés | MEDLINE | ID: mdl-33795428

RESUMEN

T cell exhaustion limits immune responses against cancer and is a major cause of resistance to chimeric antigen receptor (CAR)-T cell therapeutics. Using murine xenograft models and an in vitro model wherein tonic CAR signaling induces hallmark features of exhaustion, we tested the effect of transient cessation of receptor signaling, or rest, on the development and maintenance of exhaustion. Induction of rest through enforced down-regulation of the CAR protein using a drug-regulatable system or treatment with the multikinase inhibitor dasatinib resulted in the acquisition of a memory-like phenotype, global transcriptional and epigenetic reprogramming, and restored antitumor functionality in exhausted CAR-T cells. This work demonstrates that rest can enhance CAR-T cell efficacy by preventing or reversing exhaustion, and it challenges the notion that exhaustion is an epigenetically fixed state.


Asunto(s)
Dasatinib/farmacología , Epigénesis Genética , Inmunoterapia Adoptiva , Receptores Quiméricos de Antígenos/metabolismo , Linfocitos T/inmunología , Animales , Línea Celular Tumoral , Citotoxicidad Inmunológica , Regulación hacia Abajo , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Epigenoma , Femenino , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Proteínas del Grupo de Alta Movilidad/metabolismo , Humanos , Memoria Inmunológica , Activación de Linfocitos , Factor de Unión 1 al Potenciador Linfoide/metabolismo , Masculino , Ratones , Neoplasias Experimentales/terapia , Dominios Proteicos , Estabilidad Proteica , Receptores Quiméricos de Antígenos/química , Receptores Quiméricos de Antígenos/inmunología , Transducción de Señal , Linfocitos T/metabolismo , Transcripción Genética , Ensayos Antitumor por Modelo de Xenoinjerto
2.
Int J Nanomedicine ; 16: 2173-2186, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33758505

RESUMEN

Background: Colon cancer is a top lethal cancer in man and women worldwide and drug resistance is the major cause of cancer-related death. Combinational therapy and drug delivery with nanoparticles have been shown to effectively overcome drug resistance in many cancers. We previously reported that nanoemulsion (NE) loaded paclitaxel (PTX) and BEZ235 could synergistically inhibit colon cancer cell growth. Purpose: To investigate whether NE loaded PTX and BEZ235 can overcome drug resistance and synergistically inhibit drug-resistant colon cancer cell growth in vitro and in vivo. Methods: The in vitro treatment effect on cell viability was assayed using CCK8 kit, cell morphological change was detected by ß-tubulin immunofluorescence staining, drug resistance-related proteins were analyzed by Western blotting, and in vivo tumor growth test was performed in nude mice xeno-transplanted with 2 drug-resistant colon cancer cell lines HCT116-LOHP and HT29-DDP. Results: Both cell lines were sensitive to PTX but relatively insensitive to BEZ235. PTX combined with BEZ235 synergistically inhibited the proliferation of both cell lines. Nanoemulsion loaded PTX (NE-PTX) reduced the IC50 of PTX to approximately 2/5 of free PTX, indicating a high inhibitory efficacy of NE-PTX. When NE-PTX combined with a low concentration of BEZ235 (50 nM), the IC50 was decreased to approximately 2/3 of free PTX. Moreover, NE-PTX+BEZ235 treatment increased apoptosis, decreased Pgp and ABCC1 expression, and reduced tumor weights compared to the single drug treatment and the control group. These results suggest that nanoemulsion loaded PTX+BEZ235 can overcome drug resistance and improve the inhibitory effect on cancer cell proliferation and tumor growth. Conclusion: Our study thus provides a possible new approach to treat colon cancer patients with drug resistance.


Asunto(s)
Apoptosis , Neoplasias del Colon/tratamiento farmacológico , Resistencia a Antineoplásicos , Imidazoles/uso terapéutico , Nanopartículas/química , Paclitaxel/uso terapéutico , Inhibidores de las Quinasa Fosfoinosítidos-3/uso terapéutico , Quinolinas/uso terapéutico , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Recuento de Células , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Forma de la Célula/efectos de los fármacos , Neoplasias del Colon/patología , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Emulsiones/química , Femenino , Humanos , Imidazoles/farmacología , Concentración 50 Inhibidora , Ratones Endogámicos BALB C , Ratones Desnudos , Proteínas de Neoplasias/metabolismo , Paclitaxel/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Quinolinas/farmacología , Serina-Treonina Quinasas TOR/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
3.
Int J Nanomedicine ; 16: 1575-1586, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33664572

RESUMEN

Background: Exosomes are a type of membrane vesicles secreted by living cells. Recent studies suggest exosome-like nanovesicles (ELNVs) from fruits and vegetables are involved in tissue renewal process and functional regulation against inflammatory diseases or cancers. However, there are few reports on ELNVs derived from medicinal plants. Methods: ELNVs derived from Asparagus cochinchinensis (Lour.) Merr. (ACNVs) were isolated and characterized. Cytotoxicity, antiproliferative and apoptosis-inducing capacity of ACNVs against hepatoma carcinoma cell were assessed. The endocytosis mechanism of ACNVs was evaluated on Hep G2 cells in the presence of different endocytosis inhibitors. In vivo distribution of ACNVs was detected in healthy and tumor-bearing mice after scavenger receptors (SRs) blockade. PEG engineering of ACNVs was achieved through optimizing the pharmacokinetic profiles. In vivo antitumor activity and toxicity were evaluated in Hep G2 cell xenograft model. Results: ACNVs were isolated and purified using a differential centrifugation method accompanied by sucrose gradient ultracentrifugation. The optimized ACNVs had an average size of about 119 nm and showed a typical cup-shaped nanostructure containing lipids, proteins, and RNAs. ACNVs were found to possess specific antitumor cell proliferation activity associated with an apoptosis-inducing pathway. ACNVs could be internalized into tumor cells mainly via phagocytosis, but they were quickly cleared once entering the blood. Blocking the SRs or PEGylation decoration prolonged the blood circulation time and increased the accumulation of ACNVs in tumor sites. In vivo antitumor results showed that PEGylated ACNVs could significantly inhibit tumor growth without side effects. Conclusion: This study provides a promising functional nano platform derived from edible Asparagus cochinchinensis that can be used in antitumor therapy with negligible side effects.


Asunto(s)
Asparagaceae/química , Carcinoma Hepatocelular/patología , Exosomas/metabolismo , Neoplasias Hepáticas/patología , Nanopartículas/química , Nanotecnología , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Endocitosis/efectos de los fármacos , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Nanopartículas/efectos adversos , Nanopartículas/ultraestructura , Polietilenglicoles/química , Distribución Tisular/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
4.
Nat Commun ; 12(1): 1940, 2021 03 29.
Artículo en Inglés | MEDLINE | ID: mdl-33782411

RESUMEN

Metabolic enzymes and metabolites display non-metabolic functions in immune cell signalling that modulate immune attack ability. However, whether and how a tumour's metabolic remodelling contributes to its immune resistance remain to be clarified. Here we perform a functional screen of metabolic genes that rescue tumour cells from effector T cell cytotoxicity, and identify the embryo- and tumour-specific folate cycle enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2). Mechanistically, MTHFD2 promotes basal and IFN-γ-stimulated PD-L1 expression, which is necessary for tumourigenesis in vivo. Moreover, IFN-γ stimulates MTHFD2 through the AKT-mTORC1 pathway. Meanwhile, MTHFD2 drives the folate cycle to sustain sufficient uridine-related metabolites including UDP-GlcNAc, which promotes the global O-GlcNAcylation of proteins including cMYC, resulting in increased cMYC stability and PD-L1 transcription. Consistently, the O-GlcNAcylation level positively correlates with MTHFD2 and PD-L1 in pancreatic cancer patients. These findings uncover a non-metabolic role for MTHFD2 in cell signalling and cancer biology.


Asunto(s)
Aminohidrolasas/genética , Antígeno B7-H1/genética , Carcinogénesis/genética , Regulación Neoplásica de la Expresión Génica , Metilenotetrahidrofolato Deshidrogenasa (NADP)/genética , Enzimas Multifuncionales/genética , Neoplasias Pancreáticas/genética , Procesamiento Proteico-Postraduccional , Linfocitos T Citotóxicos/inmunología , Aminohidrolasas/antagonistas & inhibidores , Aminohidrolasas/inmunología , Animales , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/inmunología , Carcinogénesis/inmunología , Carcinogénesis/patología , Línea Celular Tumoral , Embrión de Mamíferos , Fibroblastos/inmunología , Fibroblastos/patología , Ácido Fólico/inmunología , Ácido Fólico/metabolismo , Humanos , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina/genética , Diana Mecanicista del Complejo 1 de la Rapamicina/inmunología , Metilenotetrahidrofolato Deshidrogenasa (NADP)/antagonistas & inhibidores , Metilenotetrahidrofolato Deshidrogenasa (NADP)/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Desnudos , Enzimas Multifuncionales/antagonistas & inhibidores , Enzimas Multifuncionales/inmunología , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , Cultivo Primario de Células , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/inmunología , Proteínas Proto-Oncogénicas c-myc/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/inmunología , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/inmunología , Transducción de Señal , Linfocitos T Citotóxicos/patología , Carga Tumoral , Escape del Tumor , Uridina Difosfato N-Acetilglucosamina/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
5.
Nat Commun ; 12(1): 1536, 2021 03 09.
Artículo en Inglés | MEDLINE | ID: mdl-33750776

RESUMEN

Hyperactivation of the MAPK signaling pathway motivates the clinical use of MAPK inhibitors for BRAF-mutant melanomas. Heterogeneity in differentiation state due to epigenetic plasticity, however, results in cell-to-cell variability in the state of MAPK dependency, diminishing the efficacy of MAPK inhibitors. To identify key regulators of such variability, we screen 276 epigenetic-modifying compounds, individually or combined with MAPK inhibitors, across genetically diverse and isogenic populations of melanoma cells. Following single-cell analysis and multivariate modeling, we identify three classes of epigenetic inhibitors that target distinct epigenetic states associated with either one of the lysine-specific histone demethylases Kdm1a or Kdm4b, or BET bromodomain proteins. While melanocytes remain insensitive, the anti-tumor efficacy of each inhibitor is predicted based on melanoma cells' differentiation state and MAPK activity. Our systems pharmacology approach highlights a path toward identifying actionable epigenetic factors that extend the BRAF oncogene addiction paradigm on the basis of tumor cell differentiation state.


Asunto(s)
Diferenciación Celular/efectos de los fármacos , Epigenómica/métodos , Melanoma/metabolismo , Dependencia del Oncogén , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Epigénesis Genética/efectos de los fármacos , Femenino , Histona Demetilasas/metabolismo , Humanos , Histona Demetilasas con Dominio de Jumonji/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Melanocitos/metabolismo , Melanoma/genética , Ratones , Ratones Desnudos , Mutación , Dependencia del Oncogén/genética , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas B-raf/genética , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
6.
Nat Commun ; 12(1): 1521, 2021 03 09.
Artículo en Inglés | MEDLINE | ID: mdl-33750801

RESUMEN

Resistance to next-generation anti-androgen enzalutamide (ENZ) constitutes a major challenge for the treatment of castration-resistant prostate cancer (CRPC). By performing genome-wide ChIP-seq profiling in ENZ-resistant CRPC cells we identify a set of androgen receptor (AR) binding sites with increased AR binding intensity (ARBS-gained). While ARBS-gained loci lack the canonical androgen response elements (ARE) and pioneer factor FOXA1 binding motifs, they are highly enriched with CpG islands and the binding sites of unmethylated CpG dinucleotide-binding protein CXXC5 and the partner TET2. RNA-seq analysis reveals that both CXXC5 and its regulated genes including ID1 are upregulated in ENZ-resistant cell lines and these results are further confirmed in patient-derived xenografts (PDXs) and patient specimens. Consistent with the finding that ARBS-gained loci are highly enriched with H3K27ac modification, ENZ-resistant PCa cells, organoids, xenografts and PDXs are hyper-sensitive to NEO2734, a dual inhibitor of BET and CBP/p300 proteins. These results not only reveal a noncanonical AR function in acquisition of ENZ resistance, but also posit a treatment strategy to target this vulnerability in ENZ-resistant CRPC.


Asunto(s)
Feniltiohidantoína/análogos & derivados , Feniltiohidantoína/farmacología , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/metabolismo , Antagonistas de Andrógenos/farmacología , Antagonistas de Receptores de Angiotensina , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Animales , Sitios de Unión , Proliferación Celular/efectos de los fármacos , Proteínas de Unión al ADN/metabolismo , Factor Nuclear 3-alfa del Hepatocito/metabolismo , Humanos , Masculino , Ratones , Ratones SCID , Organoides , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Transducción de Señal/efectos de los fármacos , Factores de Transcripción/metabolismo , Regulación hacia Arriba , Ensayos Antitumor por Modelo de Xenoinjerto
7.
Nat Commun ; 12(1): 1541, 2021 03 09.
Artículo en Inglés | MEDLINE | ID: mdl-33750829

RESUMEN

Pancreatic ductal adenocarcinoma (PDAC) is characterized by marked desmoplasia and drug resistance due, in part, to poor drug delivery to extravascular tumor tissue. Here, we report that carcinoma-associated fibroblasts (CAFs) induce ß5 integrin expression in tumor cells in a TGF-ß dependent manner, making them an efficient drug delivery target for the tumor-penetrating peptide iRGD. The capacity of iRGD to deliver conjugated and co-injected payloads is markedly suppressed when ß5 integrins are knocked out in the tumor cells. Of note, ß5 integrin knock-out in tumor cells leads to reduced disease burden and prolonged survival of the mice, demonstrating its contribution to PDAC progression. iRGD significantly potentiates co-injected chemotherapy in KPC mice with high ß5 integrin expression and may be a powerful strategy to target an aggressive PDAC subpopulation.


Asunto(s)
Cadenas beta de Integrinas/genética , Cadenas beta de Integrinas/metabolismo , Neoplasias Pancreáticas/metabolismo , Animales , Fibroblastos Asociados al Cáncer , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Progresión de la Enfermedad , Sistemas de Liberación de Medicamentos , Quimioterapia , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones , Ratones Endogámicos C57BL , Oligopéptidos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Microambiente Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto
8.
Nat Commun ; 12(1): 1812, 2021 03 22.
Artículo en Inglés | MEDLINE | ID: mdl-33753739

RESUMEN

Human hexokinase 2 is an essential regulator of glycolysis that couples metabolic and proliferative activities in cancer cells. The binding of hexokinase 2 to the outer membrane of mitochondria is critical for its oncogenic activity. However, the regulation of hexokinase 2 binding to mitochondria remains unclear. Here, we report that SUMOylation regulates the binding of hexokinase 2 to mitochondria. We find that hexokinase 2 can be SUMOylated at K315 and K492. SUMO-specific protease SENP1 mediates the de-SUMOylation of hexokinase 2. SUMO-defective hexokinase 2 preferably binds to mitochondria and enhances both glucose consumption and lactate production and decreases mitochondrial respiration in parallel. This metabolic reprogramming supports prostate cancer cell proliferation and protects cells from chemotherapy-induced cell apoptosis. Moreover, we demonstrate an inverse relationship between SENP1-hexokinase 2 axis and chemotherapy response in prostate cancer samples. Our data provide evidence for a previously uncovered posttranslational modification of hexokinase 2 in cancer cells, suggesting a potentially actionable strategy for preventing chemotherapy resistance in prostate cancer.


Asunto(s)
Carcinogénesis/metabolismo , Hexoquinasa/metabolismo , Mitocondrias/metabolismo , Neoplasias de la Próstata/metabolismo , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Carcinogénesis/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cisteína Endopeptidasas/genética , Cisteína Endopeptidasas/metabolismo , Docetaxel/farmacología , Hexoquinasa/genética , Humanos , Masculino , Ratones , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Unión Proteica , Sumoilación , Ensayos Antitumor por Modelo de Xenoinjerto/métodos
9.
J Vis Exp ; (168)2021 02 09.
Artículo en Inglés | MEDLINE | ID: mdl-33645559

RESUMEN

The efficacy of photoimmunotherapy can be evaluated more accurately with an orthotopic mouse model than with a subcutaneous one. A pleural dissemination model can be used for the evaluation of treatment methods for intrathoracic diseases such as lung cancer or malignant pleural mesothelioma. Near-infrared photoimmunotherapy (NIR-PIT) is a recently developed cancer treatment strategy that combines the specificity of tumor-targeting antibodies with toxicity caused by a photoabsorber (IR700Dye) after exposure to NIR light. The efficacy of NIR-PIT has been reported using various antibodies; however, only a few reports have shown the therapeutic effect of this strategy in an orthotopic model. In the present study, we demonstrate an example of efficacy evaluation of the pleural disseminated lung cancer model, which was treated using NIR-PIT.


Asunto(s)
Inmunoterapia/métodos , Neoplasias Pulmonares/terapia , Fármacos Fotosensibilizantes/uso terapéutico , Fototerapia/métodos , Neoplasias Pleurales/terapia , Animales , Terapia Combinada , Modelos Animales de Enfermedad , Femenino , Humanos , Inmunoconjugados/uso terapéutico , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Ratones , Ratones Desnudos , Neoplasias Pleurales/inmunología , Neoplasias Pleurales/patología , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
10.
Science ; 371(6533)2021 03 05.
Artículo en Inglés | MEDLINE | ID: mdl-33649166

RESUMEN

TP53 (tumor protein p53) is the most commonly mutated cancer driver gene, but drugs that target mutant tumor suppressor genes, such as TP53, are not yet available. Here, we describe the identification of an antibody highly specific to the most common TP53 mutation (R175H, in which arginine at position 175 is replaced with histidine) in complex with a common human leukocyte antigen-A (HLA-A) allele on the cell surface. We describe the structural basis of this specificity and its conversion into an immunotherapeutic agent: a bispecific single-chain diabody. Despite the extremely low p53 peptide-HLA complex density on the cancer cell surface, the bispecific antibody effectively activated T cells to lyse cancer cells that presented the neoantigen in vitro and in mice. This approach could in theory be used to target cancers containing mutations that are difficult to target in conventional ways.


Asunto(s)
Anticuerpos Biespecíficos/inmunología , Anticuerpos Antineoplásicos/inmunología , Antígenos de Neoplasias/inmunología , Antígeno HLA-A2/inmunología , Neoplasias/terapia , Proteína p53 Supresora de Tumor/inmunología , Alelos , Animales , Anticuerpos Biespecíficos/química , Anticuerpos Biespecíficos/uso terapéutico , Anticuerpos Antineoplásicos/química , Anticuerpos Antineoplásicos/uso terapéutico , Arginina/genética , Células COS , Chlorocebus aethiops , Femenino , Células HEK293 , Antígeno HLA-A2/química , Antígeno HLA-A2/genética , Histidina/genética , Humanos , Inmunización Pasiva , Células Jurkat , Activación de Linfocitos , Ratones Endogámicos NOD , Mutación , Linfocitos T/inmunología , Proteína p53 Supresora de Tumor/química , Proteína p53 Supresora de Tumor/genética , Ensayos Antitumor por Modelo de Xenoinjerto
11.
J Med Chem ; 64(3): 1570-1583, 2021 02 11.
Artículo en Inglés | MEDLINE | ID: mdl-33523674

RESUMEN

Androgen receptor (AR) contributes to the progression of glioblastoma (GBM), and antiandrogen agents have the potential to be used for the treatment of GBM. However, AR mutation commonly happens in GBM, which makes the antiandrogen agents less effective. Heat shock 27 kDa protein (HSP27) is a well-documented chaperone protein to stabilize ARs. Inhibition of HSP27 results in AR degradation regardless of the mutation status of ARs, which makes HSP27 a good target to abolish ARs in GBM. Compound I is a HSP27 inhibitor that significantly induces AR degradation in GBM cells via the proteasomal pathway, and it selectively inhibits AR-overexpressed GBM cell growth with IC50 values around 5 nM. The compound also significantly inhibits in vivo GBM xenograft at 20 mg/kg and does not cause toxicity to mice up to 80 mg/kg. These results suggest that targeting HSP27 to induce AR degradation in GBM is a promising and novel treatment.


Asunto(s)
Antagonistas de Andrógenos/farmacología , Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Proteínas de Choque Térmico HSP27/antagonistas & inhibidores , Receptores Androgénicos/efectos de los fármacos , Antagonistas de Andrógenos/toxicidad , Animales , Neoplasias Encefálicas/genética , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos , Diseño de Fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glioblastoma/genética , Humanos , Ratones , Modelos Moleculares , Simulación del Acoplamiento Molecular , Mutación , Complejo de la Endopetidasa Proteasomal/efectos de los fármacos , Receptores Androgénicos/genética , Bibliotecas de Moléculas Pequeñas , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de Xenoinjerto
12.
J Med Chem ; 64(3): 1701-1712, 2021 02 11.
Artículo en Inglés | MEDLINE | ID: mdl-33529017

RESUMEN

Glutathione transferase (GST P1-1) is a potential target for anticancer drugs. In this work, a series of 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) derivatives as GST P1-1 inhibitors were designed, synthesized, and evaluated for their biological activity. Among the target compounds, 4n showed more selective inhibition toward GST P1-1 and GST M2-2, better water solubility, and more potent anticancer activities toward all the tested cancer cells (except for HOS) than its parent molecule. Detailed biological studies on the effect of 4n toward 143b cells revealed that 4n could arrest the cell cycle at the G2 phase and induced cell apoptosis in a dose-dependent manner. Like NBDHEX, 4n displayed good pharmacokinetic characteristics. An in vivo study on 143b xenograft models demonstrated that 4n could significantly reduce tumor growth in a dose-dependent manner, showing stronger antitumor activity than NBDHEX. Thus, 4n deserves to be further investigated as a potential antitumor agent for cancer therapy.


Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Glutatión Transferasa/antagonistas & inhibidores , Animales , Antineoplásicos/toxicidad , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Resistencia a Antineoplásicos/efectos de los fármacos , Inhibidores Enzimáticos/toxicidad , Fase G2/efectos de los fármacos , Humanos , Simulación del Acoplamiento Molecular , Ratas , Ratas Sprague-Dawley , Solubilidad , Ensayos Antitumor por Modelo de Xenoinjerto
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.
J Med Chem ; 64(3): 1725-1732, 2021 02 11.
Artículo en Inglés | MEDLINE | ID: mdl-33529029

RESUMEN

A pyridone-derived phosphate prodrug of an enhancer of zeste homolog 2 (EZH2) inhibitor was designed and synthesized to improve the inhibitor's aqueous solubility. This prodrug (compound 5) was profiled in pharmacokinetic experiments to assess its ability to deliver the corresponding parent compound (compound 2) to animals in vivo following oral administration. Results from these studies showed that the prodrug was efficiently converted to its parent compound in vivo. In separate experiments, the prodrug demonstrated impressive in vivo tumor growth inhibition in a diffuse large B-cell lymphoma Karpas-422 cell line-derived xenograft model. The described prodrug strategy is expected to be generally applicable to poorly soluble pyridone-containing EZH2 inhibitors and provides a new option to enable such compounds to achieve sufficiently high exposures in vivo.


Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Proteína Potenciadora del Homólogo Zeste 2/antagonistas & inhibidores , Profármacos/síntesis química , Profármacos/farmacología , Piridonas/síntesis química , Piridonas/farmacología , Animales , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Diseño de Fármacos , Humanos , Linfoma de Células B/tratamiento farmacológico , Ratones , Modelos Moleculares , Profármacos/farmacocinética , Piridonas/farmacocinética , Ratas , Ensayos Antitumor por Modelo de Xenoinjerto
15.
Gene ; 779: 145493, 2021 May 05.
Artículo en Inglés | MEDLINE | ID: mdl-33588034

RESUMEN

Liver cancer is a malignant disease and causes thousands of death each year. The prognosis is dismal for patients with metastasis and recurrence. It is urgent to disclose the cause and mechanism underlying liver cancer. LARGE1 encodes a glycosyltransferase and was reported to promote progression in cancer. But its role in liver cancer is unknown. In this study, LARGE1 displayed upregulated expression in liver cancer cells. When LARGE1 was knocked down in SMMC-7721 and Huh-7 cells, the ability of cell proliferation and colony formation were decreased significantly. Cell migration and invasion were suppressed. The number of cells in G1 phase increased but decreased in S phase. Cell apoptosis was not affected. Tumor growth in vivo was also inhibited. Tumor volume was decreased from 1270 mm3 to 721 mm3 (p < 0.05) and tumor weight from 0.95 g to 0.63 g (p < 0.05). Furthermore, the expression of ß-catenin, TCF and Cyclin D1 was reduced when LARGE1 was knocked down but increased in LARGE1-overexpressed cells. LGK-974, a specific inhibitor in canonical Wnt signaling, inhibited cell proliferation even when LARGE1 was over-expressed. In tumor tissues, LARGE1 was increased by 4.8 folds compared to paratumoral tissues. And higher LARGE1 expression caused shorter survival. Clinicopathological analysis demonstrated that LARGE1 was associated with TNM stage (Ⅰ/Ⅱ vs III/IV, p = 0.005). Therefore, LARGE1 promotes progression and regulates Wnt/ß-catenin signaling pathway in liver cancer.


Asunto(s)
Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , N-Acetilglucosaminiltransferasas/genética , Animales , Apoptosis/genética , Ciclo Celular/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Neoplasias Hepáticas/mortalidad , Masculino , Ratones Desnudos , Persona de Mediana Edad , Vía de Señalización Wnt/genética , Ensayos Antitumor por Modelo de Xenoinjerto
16.
Cancer Treat Rev ; 94: 102157, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33607461

RESUMEN

A major breakthrough in cancer immunotherapy was the development of monoclonal antibodies targeting inhibitory immune checkpoint proteins. This approach demonstrated significant antitumor activity and efficacy in different cancer types, including metastatic renal cell carcinoma (mRCC). In the majority of patients, this drug is able to restore the patient's tumour-specific T-cell-mediated response thus improving both overall survival and objective response rate. However, a lack of clinical response occurs in a number of patients, raising questions about how to predict and increase the number of patients who receive long-term clinical benefit from immune checkpoint therapy or not. The aim of this review is to summarize available data about immune biomarkers in patients with mRCC treated with immunotherapy.


Asunto(s)
Antineoplásicos Inmunológicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Animales , Antígeno B7-H1/biosíntesis , Antígeno B7-H1/inmunología , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/inmunología , Carcinoma de Células Renales/patología , Ensayos Clínicos Fase III como Asunto , Humanos , Neoplasias Renales/genética , Neoplasias Renales/inmunología , Neoplasias Renales/patología , Valor Predictivo de las Pruebas , Ensayos Clínicos Controlados Aleatorios como Asunto , Transcriptoma , Ensayos Antitumor por Modelo de Xenoinjerto
17.
Nature ; 590(7846): 504-508, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33536620

RESUMEN

Amplification of chromosomal region 8p11-12 is a common genetic alteration that has been implicated in the aetiology of lung squamous cell carcinoma (LUSC)1-3. The FGFR1 gene is the main candidate driver of tumorigenesis within this region4. However, clinical trials evaluating FGFR1 inhibition as a targeted therapy have been unsuccessful5. Here we identify the histone H3 lysine 36 (H3K36) methyltransferase NSD3, the gene for which is located in the 8p11-12 amplicon, as a key regulator of LUSC tumorigenesis. In contrast to other 8p11-12 candidate LUSC drivers, increased expression of NSD3 correlated strongly with its gene amplification. Ablation of NSD3, but not of FGFR1, attenuated tumour growth and extended survival in a mouse model of LUSC. We identify an LUSC-associated variant NSD3(T1232A) that shows increased catalytic activity for dimethylation of H3K36 (H3K36me2) in vitro and in vivo. Structural dynamic analyses revealed that the T1232A substitution elicited localized mobility changes throughout the catalytic domain of NSD3 to relieve auto-inhibition and to increase accessibility of the H3 substrate. Expression of NSD3(T1232A) in vivo accelerated tumorigenesis and decreased overall survival in mouse models of LUSC. Pathological generation of H3K36me2 by NSD3(T1232A) reprograms the chromatin landscape to promote oncogenic gene expression signatures. Furthermore, NSD3, in a manner dependent on its catalytic activity, promoted transformation in human tracheobronchial cells and growth of xenografted human LUSC cell lines with amplification of 8p11-12. Depletion of NSD3 in patient-derived xenografts from primary LUSCs containing NSD3 amplification or the NSD3(T1232A)-encoding variant attenuated neoplastic growth in mice. Finally, NSD3-regulated LUSC-derived xenografts were hypersensitive to bromodomain inhibition. Thus, our work identifies NSD3 as a principal 8p11-12 amplicon-associated oncogenic driver in LUSC, and suggests that NSD3-dependency renders LUSC therapeutically vulnerable to bromodomain inhibition.


Asunto(s)
Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , N-Metiltransferasa de Histona-Lisina/metabolismo , Histonas/química , Histonas/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Proteínas Nucleares/metabolismo , Animales , Biocatálisis , Carcinogénesis/genética , Carcinoma de Células Escamosas/genética , Femenino , N-Metiltransferasa de Histona-Lisina/deficiencia , N-Metiltransferasa de Histona-Lisina/genética , Humanos , Neoplasias Pulmonares/genética , Masculino , Metilación , Ratones , Modelos Moleculares , Mutación , Proteínas Nucleares/deficiencia , Proteínas Nucleares/genética , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/deficiencia , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
18.
Life Sci ; 271: 119149, 2021 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-33549596

RESUMEN

Drug resistance in cancer, still poses therapeutic challenges and tumor microenvironment plays a critical role in it. Microvesicles (MVs) are effective transporters of the molecular information between cells and regulate the tumor microenvironment. They contribute to the drug resistance by transferring functional molecules between cells. Herein we report the effects of liver cancer cell-secreted MVs on sorafenib resistance in liver cancer cells HepG2 and Huh7 both in vitro and in vivo. In our study, these cancer cell-secreted MVs affected the anti-proliferative effect of sorafenib in a dose- and time-dependent manner and also inhibited the sorafenib induced apoptosis in vitro. Further, in in-vivo xenograft mice models, liver cancer cell-secreted MVs increased the tumor volume even after sorafenib treatment. Further, HGF, also got elevated in liver cancer cell-secreted MVs treatment group and activated Ras protein expression. miR-25 in the cancer cell-secreted MVs was transferred to their host cells HepG2 and Huh7 cells and reversed the sorafenib induced expression of tumor suppressor p53. This in turn induced the expression of FOXM1, a key regulator of cell cycle progression and thus affected the anti-proliferative effect of sorafenib. Therefore, this study reveals that liver cancer cell-derived MVs can mediate sorafenib resistance in the liver cancer cells, suggesting that these MVs may not be utilized as vehicles for anti-cancer drug delivery in liver cancer treatments.


Asunto(s)
Micropartículas Derivadas de Células/metabolismo , Resistencia a Antineoplásicos/fisiología , Proteína Forkhead Box M1/biosíntesis , Neoplasias Hepáticas/metabolismo , Sorafenib/farmacología , Proteína p53 Supresora de Tumor/metabolismo , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Regulación Neoplásica de la Expresión Génica , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Sorafenib/uso terapéutico , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Ensayos Antitumor por Modelo de Xenoinjerto/métodos
19.
Life Sci ; 271: 119185, 2021 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-33577846

RESUMEN

AIMS: Melanoma is a malignant tumor of the skin with a high metastasis rate and poor prognosis. Glaucocalyxin A (GLA), isolated from Rabdosia japonica, is a diterpenoid compound with anticancer properties. Here, we investigated the anticancer properties and explored the mechanisms underlying GLA activity in melanoma cells in vitro and in vivo. MAIN METHODS: Cell Counting Kit-8 and colony formation assays were used to assess the effects of GLA on cell proliferation. Flow cytometry was used to evaluate the cell cycle, apoptosis, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS), and western blot analysis and immunofluorescence staining were used to examine protein expression. Immunohistochemical analysis was performed to examine animal tissues and tumors in mice. KEY FINDINGS: GLA could effectively inhibit cell proliferation and induce cell apoptosis. GLA induced an overproduction of cellular ROS, decreased MMP, and upregulated the Bax/Bcl-2 ratio, which is an indicator of apoptosis. Phosphorylation of nuclear factor κB (NF-κB)/p65 and NF-κB/p65 nuclear expression decreased after GLA treatment in vitro and in vivo, suggesting that the anticancer effects of GLA are mediated through the NF-κB/p65 pathway. Moreover, we observed that GLA was effective in inhibiting tumor growth without obvious toxicity to major organs in mice. SIGNIFICANCE: This is the first study to show that GLA inhibits cell proliferation, arrests the cell cycle in the G2/M phase, and induces mitochondrial apoptosis via the NF-κB/p65 pathway in melanoma cells. Overall, our results demonstrate that GLA may be a potential anticancer agent for the treatment of melanoma.


Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Diterpenos de Tipo Kaurano/farmacología , Melanoma/metabolismo , Factor de Transcripción ReIA/metabolismo , Animales , Antineoplásicos/uso terapéutico , Apoptosis/fisiología , Puntos de Control del Ciclo Celular/fisiología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Diterpenos de Tipo Kaurano/uso terapéutico , Relación Dosis-Respuesta a Droga , Humanos , Melanoma/tratamiento farmacológico , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Factor de Transcripción ReIA/antagonistas & inhibidores , Ensayos Antitumor por Modelo de Xenoinjerto/métodos
20.
Nat Metab ; 3(2): 182-195, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33619381

RESUMEN

Head and neck squamous cell carcinoma (SCC) remains among the most aggressive human cancers. Tumour progression and aggressiveness in SCC are largely driven by tumour-propagating cells (TPCs). Aerobic glycolysis, also known as the Warburg effect, is a characteristic of many cancers; however, whether this adaptation is functionally important in SCC, and at which stage, remains poorly understood. Here, we show that the NAD+-dependent histone deacetylase sirtuin 6 is a robust tumour suppressor in SCC, acting as a modulator of glycolysis in these tumours. Remarkably, rather than a late adaptation, we find enhanced glycolysis specifically in TPCs. More importantly, using single-cell RNA sequencing of TPCs, we identify a subset of TPCs with higher glycolysis and enhanced pentose phosphate pathway and glutathione metabolism, characteristics that are strongly associated with a better antioxidant response. Together, our studies uncover enhanced glycolysis as a main driver in SCC, and, more importantly, identify a subset of TPCs as the cell of origin for the Warburg effect, defining metabolism as a key feature of intra-tumour heterogeneity.


Asunto(s)
Glucólisis , Neoplasias de Cabeza y Cuello/patología , Células Madre Neoplásicas/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Animales , Antioxidantes/metabolismo , Progresión de la Enfermedad , Glutatión/metabolismo , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Vía de Pentosa Fosfato , ARN Neoplásico/genética , Análisis de la Célula Individual , Sirtuinas/genética , Sirtuinas/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
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