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Sinonasal malignancies make up <5% of all head and neck neoplasms, with an incidence of 0.5-1.0 per 100,000. The outcome of these rare malignancies has been poor, whereas significant progress has been made in the management of other cancers. The objective of the current review was to describe the incidence, causes, presentation, diagnosis, treatment, and recent developments of malignancies of the sinonasal tract. The diagnoses covered in this review included sinonasal undifferentiated carcinoma, sinonasal adenocarcinoma, sinonasal squamous cell carcinoma, and esthesioneuroblastoma, which are exclusive to the sinonasal tract. In addition, the authors covered malignances that are likely to be encountered in the sinonasal tract-primary mucosal melanoma, NUT (nuclear protein of the testis) carcinoma, and extranodal natural killer cell/T-cell lymphoma. For the purpose of keeping this review as concise and focused as possible, sarcomas and malignancies that can be classified as salivary gland neoplasms were excluded.
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Carcinoma , Neoplasias del Seno Maxilar , Melanoma , Neoplasias Nasales , Senos Paranasales , Humanos , Carcinoma/diagnóstico , Neoplasias del Seno Maxilar/diagnóstico , Neoplasias del Seno Maxilar/patología , Cavidad Nasal/patología , Neoplasias Nasales/diagnóstico , Neoplasias Nasales/epidemiología , Neoplasias Nasales/terapia , Senos Paranasales/patologíaRESUMEN
Akt kinase plays a central role in cell growth, metabolism, and tumorigenesis. The TRAF6 E3 ligase orchestrates IGF-1-mediated Akt ubiquitination and activation. Here, we show that Akt ubiquitination is also induced by activation of ErbB receptors; unexpectedly, and in contrast to IGF-1 induced activation, the Skp2 SCF complex, not TRAF6, is a critical E3 ligase for ErbB-receptor-mediated Akt ubiquitination and membrane recruitment in response to EGF. Skp2 deficiency impairs Akt activation, Glut1 expression, glucose uptake and glycolysis, and breast cancer progression in various tumor models. Moreover, Skp2 overexpression correlates with Akt activation and breast cancer metastasis and serves as a marker for poor prognosis in Her2-positive patients. Finally, Skp2 silencing sensitizes Her2-overexpressing tumors to Herceptin treatment. Our study suggests that distinct E3 ligases are utilized by diverse growth factors for Akt activation and that targeting glycolysis sensitizes Her2-positive tumors to Herceptin treatment.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Transformación Celular Neoplásica , Proteínas F-Box/metabolismo , Glucólisis , Proteínas Quinasas Asociadas a Fase-S/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Animales , Neoplasias de la Mama/metabolismo , Modelos Animales de Enfermedad , Resistencia a Antineoplásicos , Femenino , Humanos , Ratones , Receptor ErbB-2/metabolismo , Proteínas Quinasas Asociadas a Fase-S/genética , Trastuzumab , UbiquitinaciónRESUMEN
The complex mechanism of colorectal cancer development is closely associated with epigenetic modifications and is caused by overexpression and/or inactivation of oncogenes. Histone modifying enzymes catalyze histone modifications to alter gene expression, which plays a crucial role in the development and progression of colorectal cancer. Currently, there is more frequent study on histone acetylation, methylation, and phosphorylation, and their mechanisms in colorectal cancer development are clearer. This article elaborates on the role of histone modification in epigenetics in colorectal cancer development and discusses recent advances in using it as biomarkers and therapeutic targets for the treatment of colorectal cancer. The review aims to demonstrate the significant role of histone modification as a new therapeutic target in colorectal cancer and provides insights into the novel diagnostic and therapeutic options it offers.
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BACKGROUND: Several proteins in the tripartite-motif (TRIM) family are associated with the development of colorectal cancer (CRC), but research on the role of TRIM69 was lacking. The present study examined the correlation between TRIM69 expression and colon adenocarcinoma (COAD). METHODS: mRNA sequencing data for COAD patients was extracted from The Cancer Genome Atlas to analyze correlations between TRIM69 expression and patients' clinical features as well as survival. Potential associations with immune cells and chemosensitivity also were predicted using various algorithms in the TIMER, Limma, clusterProfiler, GeneMANIA, and Gene Set Cancer Analysis platforms. Subsequently, polymerase chain reaction analysis and immunohistochemical staining were used to detect TRIM69 expression in COAD tissue samples from real-world patients. RESULTS: TRIM69 expression was lower in COAD tissues than in normal tissues and correlated with the pathologic stage and metastasis (M category). Additionally, TRIM69 was found to be involved in several immune-related pathways, notably the NOD-like signaling pathway. These results suggest that high TRIM69 expression has the potential to enhance tumor sensitivity to 5-fluorouracil and programmed cell death protein 1 (PD-1) blockers. CONCLUSIONS: From our findings that TRIM69 expression was significantly reduced in COAD compared with non-cancer tissues and associated with pathologic stage and metastasis, we conclude that increasing TRIM69 expression and/or activity may help to improve therapeutic outcomes. Accordingly, TRIM69 represents a potentially valuable marker of metastasis and target for adjuvant therapy in COAD.
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Adenocarcinoma , Neoplasias del Colon , Humanos , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/genética , Fluorouracilo/uso terapéutico , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Receptor de Muerte Celular Programada 1 , Algoritmos , Proteínas de Motivos Tripartitos/genética , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
Bladder cancer is the sixth most common cancer in the United States, with an estimated 81,400 new cases in 2020. Although bladder cancer has 4 stages, for systemic treatment we recognize 3 clinical stages: non-muscle-invasive bladder cancer (NMIBC), muscle-invasive bladder cancer (MIBC), and locally advanced/metastatic urothelial carcinoma (mUC). Approximately 70% to 80% of patients present with NMIBC at diagnosis and have an excellent 5-year overall survival (OS) of 69.2% to 95.8%.1 About 10% to 15% of patients present with MIBC at the time of diagnosis and have about a 50% chance of progressing to metastatic disease.2 mUC accounts for 10% to 15% of all bladder cancers at diagnosis, with a 5-year OS for patients of fewer than 10% with platinum-based chemotherapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunoconjugados/uso terapéutico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores de Tumor , Humanos , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inmunoconjugados/administración & dosificación , Inmunoconjugados/efectos adversos , Invasividad Neoplásica , Metástasis de la Neoplasia , Estadificación de Neoplasias , Ensayos Clínicos Controlados Aleatorios como Asunto , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
OBJECTIVE: To analyze the failure pattern and clinical efficacy of elective nodal irradiation in patients with esophageal squamous cell carcinoma who received neoadjuvant chemoradiotherapy. METHODS: We retrospectively analyzed 173 esophageal squamous cell carcinoma patients who received neoadjuvant chemoradiotherapy including elective nodal irradiation from 2002 to 2015. Failure pattern, survival and recurrence sites were analyzed. For patients with regional recurrences, the recurrence sites were analyzed in relation to an imaginary field of involved field irradiation. RESULTS: After a median follow-up of 55.5 months, 58 patients (33.5%) developed recurrences. Among 22 patients with regional recurrences, infield failure occurred in 19 patients (86.4%) and outfield failure occurred in 3 patients (13.6%), of whom only 1 patient had an outfield failure without synchronous distant metastasis. Compared with the involved field irradiation field, 6 patients' failure sites (27.3%) were located in the involved field irradiation field and 13 patients' failure sites (59.1%) were out of the involved field irradiation field but within the elective nodal irradiation field. CONCLUSIONS: Since only a minority of patients had outfield regional recurrences, neoadjuvant chemoradiotherapy with elective nodal irradiation yields satisfactory infield control. More than half of the regional recurrences occurred within the elective nodal irradiation field but out of the involved field irradiation field. Prospective evaluation of whether elective nodal irradiation could lead to an improved survival outcome is necessary.
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Carcinoma de Células Escamosas/terapia , Quimioradioterapia , Neoplasias Esofágicas/terapia , Terapia Neoadyuvante , Adulto , Anciano , Supervivencia sin Enfermedad , Carcinoma de Células Escamosas de Esófago , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Recurrencia Local de Neoplasia/terapia , Pronóstico , Estudios Retrospectivos , Insuficiencia del TratamientoRESUMEN
The homing ability of hematopoietic stem cells (HSCs) was a critical step for transplantation and subsequent hematopoiesis. Although the HSC transplantation was widely used for many diseases, the mechanism by which HSC homing was regulated remained poorly understood. F-box protein S-phase kinase associated protein2 (Skp2), a component of the Skp2-SCF E3 ligase complex, was regarded as a cell cycle regulator by controlling the level of p21 and p27 through ubiquitination. We recently reported an important role of Skp2 in maintaining HSC pool size, quiescent stage and self-renewal ability. In this current study, we showed that Skp2 was a novel and critical regulator for maintaining the homing of HSCs as well as their residence in the endosteal niche. Microarray analysis together with biochemical validations revealed that Skp2 deficiency profoundly reduced the expression of ß-catenin and its target genes. Knockdown of ß-catenin mimicked the decline of HSC homing upon Skp2 deficiency, suggesting that Skp2 may regulate ß-catenin and its target gene expression to orchestrate HSC homing. Our study not only identified Skp2 as a new regulator for maintaining ß-catenin expression and HSC homing, but also suggested that Skp2 may serve as a predictive marker for monitoring the transplantation efficiency.
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Regulación hacia Abajo , Células Madre Hematopoyéticas/citología , Proteínas Quinasas Asociadas a Fase-S/metabolismo , beta Catenina/genética , Animales , Ciclo Celular , Movimiento Celular , Células Cultivadas , Eliminación de Gen , Células Madre Hematopoyéticas/metabolismo , Ratones , Ratones Endogámicos C57BL , Proteínas Quinasas Asociadas a Fase-S/genética , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , beta Catenina/metabolismoRESUMEN
BACKGROUND: There is a strong need for early assessment of tumor response to chemotherapy in order to avoid the adverse effects of unnecessary chemotherapy and to allow early transition to second-line therapy. The purpose of this study was to determine the feasibility of ultrasonic spectral analysis for the in vivo characterization of changes in tumor microstructure in the evaluation of tumor response to chemotherapy using diagnostic ultrasound. METHODS: Experiments were approved by the regional animal care committee. Twenty-four MCF-7 breast cancer bearing nude mice were treated with adriamycin or sterile saline administered by intraperitoneal injection. Ultrasonic radio-frequency (RF) data was collected using a clinically available ultrasound scanner (6-MHz linear transducer). Linear regression parameters (spectral slope and midband-fit) regarding the calibrated power spectra from the RF signals were tested to monitor tumor response to treatment. The section equivalent to the ultrasound imaging plane was stained with hematoxylin and eosin to allow for assessment of the density of tumor cell nuclei. RESULTS: Treatment with adriamycin significantly reduced tumor growth in comparison with the control group (p = 0.003). Significant changes were observed in the ultrasonic parameters of the treated relative to the untreated tumors (p < 0.05). The spectral slope increased by 48.5%, from -10.66 ± 2.96 to -5.49 ± 2.69; the midband-fit increased by 12.8%, from -57.10 ± 7.68 to -49.81 ± 5.40. Treated tumors were associated with a significant decrease in the density of tumor cell nuclei as compared with control tumors (p < 0.001). CONCLUSIONS: Ultrasonic spectral analysis can detect changes in tumor microstructure after chemotherapy, and this will be helpful in the early evaluation tumor response to chemotherapy.
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Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/patología , Análisis Espectral/métodos , Animales , Antibióticos Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Doxorrubicina/uso terapéutico , Femenino , Análisis de Fourier , Modelos Lineales , Ratones , Ratones Desnudos , Distribución Aleatoria , Procesamiento de Señales Asistido por Computador , Método Simple Ciego , UltrasonografíaRESUMEN
Background: Although surgical methods are the most effective treatments for colon adenocarcinoma (COAD), the cure rates remain low, and recurrence rates remain high. Furthermore, platelet adhesion-related genes are gaining attention as potential regulators of tumorigenesis. Therefore, identifying the mechanisms responsible for the regulation of these genes in patients with COAD has become important. The present study aims to investigate the underlying mechanisms of platelet adhesion-related genes in COAD patients. Methods: The present study was an experimental study. Initially, the effects of platelet number and related genomic alteration on survival were explored using real-world data and the cBioPortal database, respectively. Then, the differentially expressed platelet adhesion-related genes of COAD were analyzed using the TCGA database, and patients were further classified by employing the non-negative matrix factorization (NMF) analysis method. Afterward, some of the clinical and expression characteristics were analyzed between clusters. Finally, least absolute shrinkage and selection operator regression analysis was used to establish the prognostic nomogram. All data analyses were performed using the R package. Results: High platelet counts are associated with worse survival in real-world patients, and alternations to platelet adhesion-related genes have resulted in poorer prognoses, based on online data. Based on platelet adhesion-related genes, patients with COAD were classified into two clusters by NMF-based clustering analysis. Cluster2 had a better overall survival, when compared to Cluster1. The gene copy number and enrichment analysis results revealed that two pathways were differentially enriched. In addition, the differentially expressed genes between these two clusters were enriched for POU6F1 in the transcription factor signaling pathway, and for MATN3 in the ceRNA network. Finally, a prognostic nomogram, which included the ALOX12 and ACTG1 genes, was established based on the platelet adhesion-related genes, with a concordance (C) index of 0.879 (0.848-0.910). Conclusion: The mRNA expression-based NMF was used to reveal the potential role of platelet adhesion-related genes in COAD. The series of experiments revealed the feasibility of targeting platelet adhesion-associated gene therapy.
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Epstein-Barr virus (EBV)-encoded molecules have been detected in the tumor tissues of several cancers, including nasopharyngeal carcinoma (NPC), suggesting that EBV plays an important role in tumorigenesis. However, the nature of EBV with respect to genome width in vivo and whether EBV undergoes clonal expansion in the tumor tissues are still poorly understood. In this study, next-generation sequencing (NGS) was used to sequence DNA extracted directly from the tumor tissue of a patient with NPC. Apart from the human sequences, a clinically isolated EBV genome 164.7 kb in size was successfully assembled and named GD2 (GenBank accession number HQ020558). Sequence and phylogenetic analyses showed that GD2 was closely related to GD1, a previously assembled variant derived from a patient with NPC. GD2 contains the most prevalent EBV variants reported in Cantonese patients with NPC, suggesting that it might be the prevalent strain in this population. Furthermore, GD2 could be grouped into a single subtype according to common classification criteria and contains only 6 heterozygous point mutations, suggesting the monoclonal expansion of GD2 in NPC. This study represents the first genome-wide analysis of a clinical isolate of EBV directly extracted from NPC tissue. Our study reveals that NGS allows the characterization of genome-wide variations of EBV in clinical tumors and provides evidence of monoclonal expansion of EBV in vivo. The pipeline could also be applied to the study of other pathogen-related malignancies. With additional NGS studies of NPC, it might be possible to uncover the potential causative EBV variant involved in NPC.
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ADN Viral/genética , Infecciones por Virus de Epstein-Barr/complicaciones , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/aislamiento & purificación , Neoplasias Nasofaríngeas/virología , Carcinoma , China , Análisis por Conglomerados , ADN Viral/química , Herpesvirus Humano 4/clasificación , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Datos de Secuencia Molecular , Carcinoma Nasofaríngeo , Filogenia , Análisis de Secuencia de ADN , Homología de SecuenciaRESUMEN
BACKGROUND: Epidermal growth factor receptor (EGFR) is suggested to predict the radiosensitivity and/or prognosis of human esophageal squamous cell carcinoma (ESCC). The objective of this study was to investigate the efficacy of Nimotuzumab (an anti-EGFR monoclonal antibody) on ESCC radiotherapy (RT) and underlying mechanisms. METHODS: Nimotuzumab was administrated to 2 ESCC cell lines KYSE30 and TE-1 treated with RT. Cell growth, colony formation and apoptosis were used to measure anti-proliferation effects. The method of RNA interference was used to investigate the role of insulin-like growth factor binding protein-3 (IGFBP-3) in ESCC cells radiosensitivity treated with Nimotuzumab. In vivo effect of Nimotuzumab on ESCC radiotherapy was done using a mouse xenograft model. RESULTS: Nimotuzumab enhanced radiation response of KYSE30 cells (with high EGFR expression) in vitro, as evidenced by increased radiation-inhibited cell growth and colony formation and radiation-mediated apoptosis. Mechanism study revealed that Nimotuzumab inhibited phosphorylated EGFR (p-EGFR) induced by EGF in KYSE30 cells. In addition, knockdown of IGFBP-3 by short hairpin RNA significantly reduced KYSE30 cells radiosensitivity (P<0.05), and even after the administration of Nimotuzumab, the RT response of IGFBP-3 silenced KYSE30 cells was not enhanced (P>0.05). In KYSE30 cell xenografts, Nimotuzumab combined with radiation led to significant tumor growth delay, compared with that of radiation alone (P=0.029), and also with IGFBP-3 up-regulation in tumor tissue. CONCLUSIONS: Nimotuzumab could enhance the RT effect of ESCC cells with a functional active EGFR pathway. In particular, the increased ESCC radiosensitivity by Nimotuzumab might be dependent on the up-regulation of IGFBP-3 through EGFR-dependent pathway.
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Anticuerpos Monoclonales Humanizados/farmacología , Carcinoma de Células Escamosas/metabolismo , Receptores ErbB/metabolismo , Neoplasias Esofágicas/metabolismo , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Tolerancia a Radiación , Regulación hacia Arriba , Apoptosis , Western Blotting , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Neoplasias Esofágicas/patología , Humanos , InmunohistoquímicaRESUMEN
BACKGROUND: Overexpression of the epidermal growth factor receptor (EGFR) and its ligands occur frequently in renal cell carcinoma (RCC). Combined vascular endothelial growth factor receptor (VEGF-R) and EGFR inhibition may overcome resistance to VEGF-R inhibitor monotherapy. We performed a dose-escalation phase II study of sunitinib plus erlotinib in advanced renal cell carcinoma. PATIENTS AND METHODS: Patients with metastatic clear cell or papillary RCC were eligible. Prior therapy was allowed except sunitinib or erlotinib. Three dose levels of erlotinib (50, 100, 150 mg daily) were evaluated in combination with sunitinib 50 mg. Thirty-seven patients were treated at maximum tolerated dose to determine efficacy. The primary endpoint was 8-month progression-free survival (PFS) rate. The trial was powered to assess for a difference between a median PFS of less than 50% with a targeted 70% PFS for the combination. RESULTS: The 8-month PFS rate was 40% (95% CI: 23-56). Median PFS was 5.8 months (95% CI: 4.1-9.7) and median overall survival (OS) was 26.3 months (95% CI: 16.1-34.0). The objective response rate was 22% and an additional 59% of patients had stable disease for at least 6 weeks. The most common adverse events for all grades were diarrhea, rash, fatigue, and dysgeusia. Dose reduction in 1 or both of the drugs was undertaken in 17 (46%) patients, while 5 (14%) discontinued study therapy due to toxicity. CONCLUSION: While sunitinib and erlotinib are combinable,the 8-month PFS rate did not suggest efficacy improvement over sunitinib monotherapy (NCT00425386).
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Carcinoma de Células Renales , Neoplasias Renales , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Células Renales/patología , Supervivencia sin Enfermedad , Receptores ErbB , Clorhidrato de Erlotinib/efectos adversos , Humanos , Neoplasias Renales/patología , Receptores de Factores de Crecimiento Endotelial Vascular , Sunitinib/uso terapéutico , Factor A de Crecimiento Endotelial VascularRESUMEN
Prostate cancer is common, particularly in older patients, as the risk of getting prostate cancer increases with age. Cancer therapy brings unique challenges in older patients, as this population is vulnerable to many side effects and drug interactions, and they have varying degrees of frailty, which may limit the use of these therapies. The US FDA has recently approved several novel next-generation hormonal therapies for patients with various stages of prostate cancer, giving patients more treatment options. These therapies (e.g., apalutamide, enzalutamide, darolutamide, and abiraterone) have unique side effects that the practitioner must consider when evaluating therapeutic treatments in any patient, and these side effects also affect older patients differently. Here, we review the mechanism of action and metabolism of the next-generation hormonal therapies; report efficacy and safety data from trials of these agents in non-metastatic castration-resistant prostate cancer, metastatic hormone-sensitive prostate cancer, and metastatic castration-resistant prostate cancer; and discuss the intricacies of treating older men with prostate cancer. Key takeaways include the fact that enzalutamide and apalutamide may increase the risk of falls and fractures in older patients. Abiraterone requires the concurrent use of low-dose glucocorticoids, which can lead to side effects in older patients. Lastly, drug-drug interactions should be considered in older patients using multiple medications.
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Neoplasias de la Próstata Resistentes a la Castración , Receptores Androgénicos , Anciano , Antagonistas de Andrógenos , Humanos , Masculino , FeniltiohidantoínaRESUMEN
PURPOSE: To compare survival outcomes and radiation pneumonitis (RP) between intensity-modulated radiotherapy (IMRT) and three-dimensional conformal radiotherapy (3DCRT) in patients with esophageal cancer (EC) who underwent definitive chemoradiation therapy (CRT). METHODS: Clinical characteristics and dose-volume histogram parameters were collected for 388 EC patients who received definitive CRT with either IMRT (n = 297) or 3DCRT (n = 91) from 2010 through 2017. Dosimetric parameters, survival end-points, and symptomatic RP (grade ≥2) were compared between groups. Propensity score matching (PSM) was performed to balance potential confounding factors. Univariate and multivariate logistic regression analyses were applied to identify predictors of RP. RESULTS: Compared with 3DCRT, IMRT was significantly associated with better overall survival (OS; P = 0.001), progression-free survival (PFS; P = 0.008), and distant metastasis-free survival (P = 0.011), but not with locoregional failure-free survival (P = 0.721). Moreover, IMRT demonstrated a remarkably lower risk of RP than 3DCRT (5.4% vs 23.1%, P < 0.001). PSM analysis further confirmed the clinical benefit of IMRT. In the matched cohort, radiation modality was independently correlated with OS and PFS. On multivariate analysis, smoking history (odds ratio [OR]: 4.225, P = 0.002), primary tumor length (OR: 2.764, P = 0.049), radiation modality (OR: 10.760, P < 0.001), planning target volume (OR: 1.004, P < 0.001), and lung V20 (OR: 1.286, P = 0.002) were found to be significant predictors of RP. CONCLUSIONS: Compared with 3DCRT, IMRT was associated with more favorable survival and a reduced risk of RP after definitive CRT, supporting the routine use of IMRT for EC.
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Neoplasias Esofágicas , Neumonitis por Radiación , Radioterapia Conformacional , Radioterapia de Intensidad Modulada , Neoplasias Esofágicas/terapia , Humanos , Puntaje de Propensión , Neumonitis por Radiación/etiología , Dosificación Radioterapéutica , Planificación de la Radioterapia Asistida por Computador , Radioterapia Conformacional/efectos adversos , Radioterapia de Intensidad Modulada/efectos adversos , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Methylation of histone lysine residues plays important roles in gene expression regulation as well as cancer initiation. Lysine specific demethylase 1 (LSD1) is responsible for maintaining balanced methylation levels at histone H3 lysine 4 (H3K4). LSD1 is a drug target for certain cancers, due to important functions of methylated H3K4 or LSD1 overexpression. We report the design, synthesis, and structure-activity relationships of 3-(piperidin-4-ylmethoxy)pyridine containing compounds as potent LSD1 inhibitors with Ki values as low as 29 nM. These compounds exhibited high selectivity (>160×) against related monoamine oxidase A and B. Enzyme kinetics and docking studies suggested they are competitive inhibitors against a dimethylated H3K4 substrate and provided a possible binding mode. The potent LSD1 inhibitors can increase cellular H3K4 methylation and strongly inhibit proliferation of several leukemia and solid tumor cells with EC50 values as low as 280 nM, while they had negligible effects on normal cells.
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Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Histona Demetilasas/antagonistas & inhibidores , Piperidinas/síntesis química , Piperidinas/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Descubrimiento de Drogas , Ensayos de Selección de Medicamentos Antitumorales , Histona Demetilasas/genética , Histonas/metabolismo , Humanos , Cinética , Metilación , Modelos Moleculares , Simulación del Acoplamiento Molecular , Inhibidores de la Monoaminooxidasa/síntesis química , Inhibidores de la Monoaminooxidasa/farmacología , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
BACKGROUND: Mixed lineage leukemia (MLL) gene translocations are found in ~75% infant and 10% adult acute leukemia, showing a poor prognosis. Lysine-specific demethylase 1 (LSD1) has recently been implicated to be a drug target for this subtype of leukemia. More studies using potent LSD1 inhibitors against MLL-rearranged leukemia are needed. METHODS: LSD1 inhibitors were examined for their biochemical and biological activities against LSD1 and MLL-rearranged leukemia as well as other cancer cells. RESULTS: Potent LSD1 inhibitors with biochemical IC50 values of 9.8-77 nM were found to strongly inhibit proliferation of MLL-rearranged leukemia cells with EC50 of 10-320 nM, while these compounds are generally non-cytotoxic to several other tumor cells. LSD1 inhibition increased histone H3 lysine 4 (H3K4) methylation, downregulated expression of several leukemia-relevant genes, induced apoptosis and differentiation, and inhibited self-renewal of stem-like leukemia cells. Moreover, LSD1 inhibitors worked synergistically with inhibition of DOT1L, a histone H3 lysine 79 (H3K79) methyltransferase, against MLL-rearranged leukemia. The most potent LSD1 inhibitor showed significant in vivo activity in a systemic mouse model of MLL-rearranged leukemia without overt toxicities. Mechanistically, LSD1 inhibitors caused significant upregulation of several pathways that promote hematopoietic differentiation and apoptosis. CONCLUSIONS: LSD1 is a drug target for MLL-rearranged leukemia, and LSD1 inhibitors are potential therapeutics for the malignancy.
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Inhibidores Enzimáticos/farmacología , Reordenamiento Génico , Histona Demetilasas/antagonistas & inhibidores , N-Metiltransferasa de Histona-Lisina/genética , Leucemia/tratamiento farmacológico , Proteína de la Leucemia Mieloide-Linfoide/genética , Animales , Western Blotting , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Niño , Sinergismo Farmacológico , Inhibidores Enzimáticos/química , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Histona Demetilasas/genética , Histona Demetilasas/metabolismo , Histonas/metabolismo , Humanos , Leucemia/genética , Leucemia/metabolismo , Lisina/metabolismo , Células MCF-7 , Metilación/efectos de los fármacos , Metiltransferasas/antagonistas & inhibidores , Metiltransferasas/genética , Metiltransferasas/metabolismo , Ratones Endogámicos NOD , Ratones SCID , Estructura Molecular , Inhibidores de la Monoaminooxidasa/química , Inhibidores de la Monoaminooxidasa/farmacología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células U937 , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Understanding the mechanism by which cell growth, migration, polyploidy, and tumorigenesis are regulated may provide important therapeutic strategies for cancer therapy. Here we identify the Skp2-macroH2A1 (mH2A1)-cyclin-dependent kinase 8 (CDK8) axis as a critical pathway for these processes, and deregulation of this pathway is associated with human breast cancer progression and patient survival outcome. We showed that mH2A1 is a new substrate of Skp2 SCF complex whose degradation by Skp2 promotes CDK8 gene and protein expression. Strikingly, breast tumour suppression on Skp2 deficiency can be rescued by mH2A1 knockdown or CDK8 restoration using mouse tumour models. We further show that CDK8 regulates p27 protein expression by facilitating Skp2-mediated p27 ubiquitination and degradation. Our study establishes a critical role of Skp2-mH2A1-CDK8 axis in breast cancer development and targeting this pathway offers a promising strategy for breast cancer therapy.
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Neoplasias de la Mama/metabolismo , Carcinogénesis/genética , Carcinoma/metabolismo , Quinasa 8 Dependiente de Ciclina/metabolismo , Puntos de Control de la Fase G2 del Ciclo Celular/genética , Histonas/metabolismo , Proteínas Quinasas Asociadas a Fase-S/genética , Animales , Línea Celular Tumoral , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Fibroblastos , Humanos , Ratones , Ratones Noqueados , Proteínas Quinasas Asociadas a Fase-S/metabolismo , Proteínas Ligasas SKP Cullina F-box/metabolismo , UbiquitinaciónRESUMEN
K63-linked ubiquitination of Akt is a posttranslational modification that plays a critical role in growth factor-mediated membrane recruitment and activation of Akt. Although E3 ligases involved in growth factor-induced ubiquitination of Akt have been defined, the deubiquitinating enzyme (DUB) that triggers deubiquitination of Akt and the function of Akt deubiquitination remain largely unclear. We showed that CYLD was a DUB for Akt and suppressed growth factor-mediated ubiquitination and activation of Akt. CYLD directly removed ubiquitin moieties from Akt under serum-starved conditions. CYLD dissociated from Akt upon growth factor stimulation, thereby allowing E3 ligases to induce ubiquitination and activation of Akt. CYLD deficiency also promoted cancer cell proliferation, survival, glucose uptake, and, when injected into mice, growth of prostate tumors. Our findings reveal the crucial role of cycles of ubiquitination and deubiquitination of Akt in determining its plasma membrane localization and activation--and further identify CYLD as a molecular switch for these processes.