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1.
J Cancer Res Clin Oncol ; 147(4): 1137-1144, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33550433

RESUMO

BACKGROUND: Neoplasms of the retroperitoneum that contain a major fat component may represent either benign entities, such as lipomas or angiomyolipomas, or malignancy such as liposarcoma. Distinguishing these diagnoses has important implications for management. While liposarcomas often stain positively for MDM2 and CDK4 proteins, absence of these markers can lead to diagnostic and management challenges. METHODS: We examined three cases in our institution of fat-containing masses of the retroperitoneum that lacked MDM2 and CDK4 markers to highlight the challenges in diagnosing and managing these cases. A thorough review of the literature examining radiologic and histologic features that can be used to determine that diagnosis was conducted and summarized. RESULTS: The three cases we present represent the three main diagnostic entities that can be found in among fatty tumors of the retroperitoneum: lipoma, angiomyolipoma, and liposarcoma. While radiologic features and analysis of histology helped to inform management, these cases in conjunction with the literature also illustrate the limitations of the diagnostic work up and importance also factoring the biologic behavior of the tumor in its management. CONCLUSION: Fat-containing tumors of the retroperitoneum that do not stain for MDM2 or CDK4 can pose a diagnostic challenge. Assessing radiologic and pathologic features in conjunction with the biologic behavior of these tumors should inform their management.


Assuntos
Quinase 4 Dependente de Ciclina/metabolismo , Lipoma/diagnóstico , Lipoma/terapia , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Neoplasias Retroperitoneais/diagnóstico , Neoplasias Retroperitoneais/terapia , Animais , Gerenciamento Clínico , Humanos , Lipoma/metabolismo , Neoplasias Retroperitoneais/metabolismo
2.
Life Sci ; 267: 118981, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33385409

RESUMO

AIM: 15-Hydroxy-8(17),13(E)-labdadiene-19-carboxylic acid (HLCA) isolated from Juniperus foetidissima, has been recently identified as an antiproliferative agent; however, the molecular basis of antiproliferative effects of HLCA remains unknown. To investigate it, the current study has emphasized the hypothesis that HLCA induced cell death is a consequence of intracellular reactive oxygen species (ROS) production followed by cell cycle arrest and apoptosis. MAIN METHODS: Human ovarian OVCAR-3 and Caov-4 cells were treated with various concentrations of HLCA (48 h) and the measurement of intracellular ROS was considered. Then, the potential of HLCA in promoting apoptosis was investigated via flow cytometry, western blot, and caspase activity assay. Also, the inhibitory effect of HLCA on the cell cycle was evaluated using flow cytometry and western blot analysis. KEY FINDINGS: We found intracellular (ROS) accumulation in HLCA-treated cells. Subsequent observation of the increment in pro-apoptotic Bax as well as the decrement in antiapoptotic Bcl2 revealed that the HLCA-induced cytotoxicity may be triggered by the intrinsic pathway of apoptosis. Our subsequent experiments suggested that caspase-9 and -3 were activated and led the cells to apoptosis during the process. Cell cycle disruption at the G1 phase via down-regulation of cyclin D1 and Cyclin-dependent kinase 4 (CDK4) was another proved mechanism by which HLCA exerts its antiproliferative effects on the ovarian cell lines, OVCAR-3 and Caov-4, especially at relatively lower concentrations. SIGNIFICANCE: This is the first study that reveals the apoptotic effects of HLCA, suggesting its therapeutic potential as an effective anti-tumor agent. However, further in vivo studies are required to confirm these effects.


Assuntos
Diterpenos/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Epitelial do Ovário , Caspase 9/metabolismo , Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclina D1/metabolismo , Quinase 4 Dependente de Ciclina/metabolismo , Diterpenos/isolamento & purificação , Feminino , Humanos , Juniperus/química , Neoplasias Ovarianas/metabolismo , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo
3.
Artigo em Inglês | MEDLINE | ID: mdl-33353034

RESUMO

The purpose of the present study was to estimate the prevalence of cyclin-dependent kinase (CDK) 4/6 inhibitors use among cancer patients from the medication-related osteonecrosis of the jaw (MRONJ) cohort of the University of Messina. We retrospectively reviewed the records of all patients with either intravenous bisphosphonates or denosumab-related MRONJ reported in the electronic health records of the Unit of Oral Surgery, School of Dentistry, University of Messina between the first quarter of 2018 and the first quarter 2020 to identify eligible patients. We observed six cases of MRONJ associated with CDK4/6 inhibitors concomitantly with intravenous bisphosphonates and/or denosumab in breast cancer patients. The CDK4/6 inhibitors registered were palbociclib (n = 5) and abemaciclib (n = 1). Data of cancer patients diagnosed with MRONJ in the same period (n = 10) were extracted for comparison. The comparative assessment with this group of patients showed a similar distribution of MRONJ stage ranged and clinical course after treatment. The degree of risk for osteonecrosis in patients taking these new classes of drugs is uncertain but warrants awareness and close monitoring. The role of premedication dental evaluation as a prevention strategy has been acknowledged for cancer patients about to initiate intravenous bisphosphonates and/or denosumab for treatment of bone metastasis, but additional attention should be paid to whom are assuming CDK4/6 inhibitors because of their oral adverse events.


Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/metabolismo , Quinase 4 Dependente de Ciclina/metabolismo , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/epidemiologia , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/etiologia , Conservadores da Densidade Óssea/efeitos adversos , Difosfonatos/efeitos adversos , Feminino , Humanos , Arcada Osseodentária , Masculino , Estudos Retrospectivos
4.
Nat Commun ; 11(1): 5305, 2020 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-33082317

RESUMO

Cell-cycle entry relies on an orderly progression of signaling events. To start, cells first activate the kinase cyclin D-CDK4/6, which leads to eventual inactivation of the retinoblastoma protein Rb. Hours later, cells inactivate APC/CCDH1 and cross the final commitment point. However, many cells with genetically deleted cyclin Ds, which activate and confer specificity to CDK4/6, can compensate and proliferate. Despite its importance in cancer, how this entry mechanism operates remains poorly characterized, and whether cells use this path under normal conditions remains unknown. Here, using single-cell microscopy, we demonstrate that cells with acutely inhibited CDK4/6 enter the cell cycle with a slowed and fluctuating cyclin E-CDK2 activity increase. Surprisingly, with low CDK4/6 activity, the order of APC/CCDH1 and Rb inactivation is reversed in both cell lines and wild-type mice. Finally, we show that as a consequence of this signaling inversion, Rb inactivation replaces APC/CCDH1 inactivation as the point of no return. Together, we elucidate the molecular steps that enable cell-cycle entry without CDK4/6 activity. Our findings not only have implications in cancer resistance, but also reveal temporal plasticity underlying the G1 regulatory circuit.


Assuntos
Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Fase G1 , Animais , Linhagem Celular , Proliferação de Células , Quinase 4 Dependente de Ciclina/genética , Quinase 6 Dependente de Ciclina/genética , Feminino , Humanos , Masculino , Camundongos , Proteína do Retinoblastoma/genética , Proteína do Retinoblastoma/metabolismo , Transdução de Sinais
5.
Adv Cancer Res ; 148: 147-169, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32723562

RESUMO

The mammalian cell cycle is driven by a complex of cyclins and their associated cyclin-dependent kinases (CDKs). Abnormal dysregulation of cyclin-CDK is a hallmark of cancer. D-type cyclins and their associated CDKs (CDK4 and CDK6) are key components of cell cycle machinery in driving G1 to S phase transition via phosphorylating and inactivating the retinoblastoma protein (RB). A body of evidence shows that the cyclin Ds-CDKs axis plays a critical role in cancer through various aspects, such as control of proliferation, senescence, migration, apoptosis, and angiogenesis. CDK4/6 dual-inhibitors show significant efficacy in pre-clinical or clinical cancer therapies either as single agents or in combination with hormone, chemotherapy, irradiation or immune treatments. Of note, as the associated partner of D-type cyclins, CDK6 shows multiple distinct functions from CDK4 in cancer. Depletion of the individual CDK may provide a therapeutic strategy for patients with cancer.


Assuntos
Ciclina D/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Animais , Ciclina D/metabolismo , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Humanos , Neoplasias/enzimologia , Fosforilação , Inibidores de Proteínas Quinases/farmacologia
6.
Nat Commun ; 11(1): 2760, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32488085

RESUMO

Peptides bound to class I major histocompatibility complexes (MHC) play a critical role in immune cell recognition and can trigger an antitumor immune response in cancer. Surface MHC levels can be modulated by anticancer agents, altering immunity. However, understanding the peptide repertoire's response to treatment remains challenging and is limited by quantitative mass spectrometry-based strategies lacking normalization controls. We describe an experimental platform that leverages recombinant heavy isotope-coded peptide MHCs (hipMHCs) and multiplex isotope tagging to quantify peptide repertoire alterations using low sample input. HipMHCs improve quantitative accuracy of peptide repertoire changes by normalizing for variation across analyses and enable absolute quantification using internal calibrants to determine copies per cell of MHC antigens, which can inform immunotherapy design. Applying this platform in melanoma cell lines to profile the immunopeptidome response to CDK4/6 inhibition and interferon-γ - known modulators of antigen presentation - uncovers treatment-specific alterations, connecting the intracellular response to extracellular immune presentation.


Assuntos
Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Apresentação do Antígeno , Antígenos , Linhagem Celular , Humanos , Imunoterapia , Interferon gama/farmacologia , Espectrometria de Massas , Peptídeos/imunologia , Proteômica
7.
J Food Sci ; 85(7): 2227-2235, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32485027

RESUMO

Phenolics, antioxidant activities, and antiproliferative properties of brown Hypsizygus marmoreus (brown HM) and white Hypsizygus marmoreus (white HM) were compared. The results showed that the contents of (+)-catechin, gallic acid, and protocatechuic acid of brown HM were higher than those of white HM. Moreover, brown HM had greater cellular antioxidant activity (CAA), peroxyl radical scavenging capacity (PSC), and oxygen radical absorbance capacity (ORAC) values than white HM, which demonstrated that brown HM presented a stronger antioxidant capacity. Both of brown HM and white HM showed remarkable antiproliferative activities against HepG2 cells and brown HM was proven to be the more effective. The flow cytometry results revealed that both of brown HM and white HM could induce G1 arrest and cell apoptotics in a dose-dependent manner. In addition, CyclinD1, CDK4, and Bcl-2 mRNA expression levels were downregulated with the treatment of brown HM or white HM. Taken together, our study revealed that brown HM afforded better antioxidant and antiproliferative activities than white HM and laid the foundation for potential application of Hypsizygus marmoreus as source of nutraceuticals and functional food products. PRACTICAL APPLICATION: A systematic assessment of the potential differences of phenolics, antioxidant, and antiproliferative activities between different Hypsizygus marmoreus varieties was carried out in the present study. Furthermore, our findings would present possible antiproliferative mechanism of extracts of different Hypsizygus marmoreus varieties, which may provide theoretical basis for further development and utilization of Hypsizygus marmoreus.


Assuntos
Agaricales/química , Antioxidantes/farmacologia , Inibidores do Crescimento/farmacologia , Fenóis/farmacologia , Extratos Vegetais/farmacologia , Antioxidantes/química , Proliferação de Células/efeitos dos fármacos , Ciclina D1/genética , Ciclina D1/metabolismo , Quinase 4 Dependente de Ciclina/genética , Quinase 4 Dependente de Ciclina/metabolismo , Inibidores do Crescimento/química , Células Hep G2 , Humanos , Fenóis/química , Extratos Vegetais/química
8.
Cancer Sci ; 111(7): 2635-2646, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32418298

RESUMO

Lung cancer is a common type of cancer that represents a health problem worldwide; lung adenocarcinoma (LUAD) is a major subtype of lung cancer. Although several treatments for LUAD have been developed, the mortality rate remains high because of uncontrollable progression. Further biological and clinicopathological studies are therefore needed. Here, we investigated the role of family with sequence similarity 111 member B (FAM111B), which is highly expressed in papillary-predominant LUAD; however, its role in cancer is unclear. An immunohistochemical analysis confirmed that papillary-predominant adenocarcinomas exhibited higher expression of FAM111B, compared with lepidic-predominant adenocarcinomas. Additionally, FAM111B expression was significantly correlated with clinical progression. In vitro functional analyses using FAM111B-knockout cells demonstrated that FAM111B plays an important role in proliferation and cell cycle progression of KRAS-driven LUAD under serum-starvation conditions. Furthermore, FAM111B regulated cyclin D1-CDK4-dependent cell cycle progression by degradation of p16. In summary, we revealed the clinical importance of FAM111B in human tumor tissues, as well as its function as a degradative enzyme. Therefore, FAM111B has potential as a clinicopathological prognostic marker for LUAD.


Assuntos
Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Proteínas de Ciclo Celular/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Adenocarcinoma de Pulmão/patologia , Idoso , Idoso de 80 Anos ou mais , Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Ciclina D/metabolismo , Quinase 4 Dependente de Ciclina/metabolismo , Feminino , Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Carga Tumoral
9.
Nat Commun ; 11(1): 2350, 2020 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-32393766

RESUMO

BET inhibitors are promising therapeutic agents for the treatment of triple-negative breast cancer (TNBC), but the rapid emergence of resistance necessitates investigation of combination therapies and their effects on tumor evolution. Here, we show that palbociclib, a CDK4/6 inhibitor, and paclitaxel, a microtubule inhibitor, synergize with the BET inhibitor JQ1 in TNBC lines. High-complexity DNA barcoding and mathematical modeling indicate a high rate of de novo acquired resistance to these drugs relative to pre-existing resistance. We demonstrate that the combination of JQ1 and palbociclib induces cell division errors, which can increase the chance of developing aneuploidy. Characterizing acquired resistance to combination treatment at a single cell level shows heterogeneous mechanisms including activation of G1-S and senescence pathways. Our results establish a rationale for further investigation of combined BET and CDK4/6 inhibition in TNBC and suggest novel mechanisms of action for these drugs and new vulnerabilities in cells after emergence of resistance.


Assuntos
Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos , Proteínas/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Azepinas/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Clonais , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , DNA de Neoplasias/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Camundongos , Modelos Biológicos , Mutação/genética , Paclitaxel/farmacologia , Piperazinas/farmacologia , Ploidias , Proteínas/metabolismo , Piridinas/farmacologia , Proteína do Retinoblastoma/genética , Proteína do Retinoblastoma/metabolismo , Resultado do Tratamento , Triazóis/farmacologia , Neoplasias de Mama Triplo Negativas/genética , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
10.
Cell ; 181(2): 424-441.e21, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32234521

RESUMO

KRAS mutant pancreatic ductal adenocarcinoma (PDAC) is characterized by a desmoplastic response that promotes hypovascularity, immunosuppression, and resistance to chemo- and immunotherapies. We show that a combination of MEK and CDK4/6 inhibitors that target KRAS-directed oncogenic signaling can suppress PDAC proliferation through induction of retinoblastoma (RB) protein-mediated senescence. In preclinical mouse models of PDAC, this senescence-inducing therapy produces a senescence-associated secretory phenotype (SASP) that includes pro-angiogenic factors that promote tumor vascularization, which in turn enhances drug delivery and efficacy of cytotoxic gemcitabine chemotherapy. In addition, SASP-mediated endothelial cell activation stimulates the accumulation of CD8+ T cells into otherwise immunologically "cold" tumors, sensitizing tumors to PD-1 checkpoint blockade. Therefore, in PDAC models, therapy-induced senescence can establish emergent susceptibilities to otherwise ineffective chemo- and immunotherapies through SASP-dependent effects on the tumor vasculature and immune system.


Assuntos
Envelhecimento/fisiologia , Carcinoma Ductal Pancreático/patologia , Remodelação Vascular/fisiologia , Animais , Linfócitos T CD8-Positivos/imunologia , Carcinoma Ductal Pancreático/microbiologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Genes ras/genética , Humanos , Imunoterapia/métodos , Sistema de Sinalização das MAP Quinases/fisiologia , Camundongos , Neoplasias Pancreáticas/patologia , Proteína do Retinoblastoma/imunologia , Transdução de Sinais/genética , Microambiente Tumoral , Remodelação Vascular/genética
11.
Eur J Med Chem ; 193: 112239, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32200202

RESUMO

CDK4/6 has been identified as an attractive therapeutic target for treatment of cancer. For unmet clinical needs, a novel class of imidazo [1',2':1,6]pyrido [2,3-d]pyrimidin derivatives, which had distinctive triheteroaryl structure, had been discovered as CDK4/6 inhibitors. The compounds 10b and 10c, displayed the low nanomolar range activities on CDK4/6, desirable antiproliferative activities, excellent metabolic properties, and acceptable pharmacokinetic characters. In Colo-205 and U87MG xenograft models, compounds 10b and 10c also showed significant tumor growth inhibitions with controllable toxicities. All data confirmed that imidazo [1',2':1,6]pyrido [2,3-d]pyrimidin derivatives 10b and 10c could be promising drug candidates for cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinas/síntese química , Pirimidinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Distribuição Tecidual
12.
Anticancer Res ; 40(3): 1419-1426, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32132038

RESUMO

BACKGROUND/AIM: Anti-cancer drug resistance restricts the efficacy of chemotherapy in malignant tumors. Casein kinase 2α (CK2α) is highly expressed in 5-fluorouracil (5FU)-resistant colorectal cancer (CRC) cells. We hypothesized that inhibition of CK2α might reduce CRC resistance to 5FU. MATERIALS AND METHODS: To investigate the role of CK2α in 5FU-resistant CRC cells, we assessed cell viability, apoptosis, cyclin-dependent kinase 4 (CDK4) activity, cell-cycle progression, invasion, and sphere formation in 5FU-resistant CRC cells. RESULTS: CK2α levels were significantly increased in 5FU-resistant CRC cells compared to those in wild-type CRC cells. During exposure to 5FU, viability, CDK4 activity, cell-cycle progression, invasion, and sphere formation were enhanced, while apoptosis was decreased in 5FU-resistant CRC cells. These effects were mediated by the inhibiting effects of CK2α on endoplasmic reticulum (ER) stress. Combination of CK2α knockdown with 5FU treatment promoted apoptosis of 5FU-resistant CRC cells by inducing ER stress. CONCLUSION: 5FU treatment in combination with a CK2α inhibitor may exert a synergistic effect against drug-resistant cancer cells.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Caseína Quinase II/antagonistas & inibidores , Neoplasias Colorretais/tratamento farmacológico , Fluoruracila/farmacologia , Caseína Quinase II/metabolismo , Linhagem Celular Tumoral , Neoplasias Colorretais/enzimologia , Quinase 4 Dependente de Ciclina/metabolismo , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fluoruracila/administração & dosagem , Humanos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia
13.
Medicine (Baltimore) ; 99(12): e19577, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32195970

RESUMO

RATIONALE: The diagnosis of anaplastic lymphoma kinase (ALK)-negative inflammatory myofibroblastic tumors (IMT) remains challenging because of their morphological resemblance with spindle cell sarcoma with myofibroblastic characteristics. PATIENT CONCERNS: A 69-year-old female patient presented with loco-regional recurrent IMT several times within 8 years after primary treatment and neck lymph node metastasis 3.5 years after last recurrence. DIAGNOSIS: The primary, recurrence, and lymph node metastasis lesions were diagnosed as ALK-negative IMTs based on the histopathological features. INTERVENTIONS: Biopsy samples were obtained during repeated surgeries and evaluated for genomic alterations during first and recurrent presentations. The evaluation was done using pathway-driven massive parallel sequencing, and genomic alterations between primary and recurrent tumors were compared. OUTCOMES: Copy number gains and overexpression of mouse double minute 2 homolog (MDM2) and cyclin dependent kinase 4 (CDK4) were observed in the primary lesion, and additional gene amplification of Discoidin Domain Receptor Tyrosine Kinase 2 (DDR2), Succinate Dehydrogenase Complex II subunit C (SDHC), and thyroid stimulating hormone receptor (TSHR) Q720H were found in the recurrent tumors. Metastases to the neck lymph node were observed 3.5 years after recurrence. LESSONS: Our results indicated genetic evolution in a microscopically benign condition and highlighted the importance of molecular characterization of fibro-inflammatory lesions of uncertain malignant potential.


Assuntos
Granuloma de Células Plasmáticas/metabolismo , Neoplasias de Cabeça e Pescoço/secundário , Recidiva Local de Neoplasia/patologia , Neoplasias de Tecido Muscular/metabolismo , Quinase do Linfoma Anaplásico/metabolismo , Quinase 4 Dependente de Ciclina/metabolismo , Diagnóstico Diferencial , Feminino , Amplificação de Genes , Granuloma de Células Plasmáticas/patologia , Neoplasias de Cabeça e Pescoço/patologia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Metástase Linfática , Mediastino/patologia , Pessoa de Meia-Idade , Miofibroblastos/patologia , Neoplasias de Tecido Muscular/patologia , Neoplasias de Tecido Muscular/radioterapia , Proteínas Proto-Oncogênicas c-mdm2/metabolismo
14.
Cancer Sci ; 111(5): 1761-1773, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32103527

RESUMO

The cyclin-dependent kinase (CDK)4/6-cyclin D1-Rb-p16/ink4a pathway is responsible for regulating cell progression past the G1 restriction point during the cell cycle. The development of a majority of human tumors is associated with dysregulation of this pathway, resulting in increased cancer cell proliferation. Both CDK4 and CDK6, well-validated cancer drug targets, function primarily as catalytic enzymes that mediate the phosphorylation of retinoblastoma protein (Rb). Here, we determined that SPH3643 is a novel potent antiproliferative agent that inhibits CDK4/6 kinase activity. In biochemical assays, SPH3643 showed more potent inhibition of both CDK4 and CDK6 than did 2 published CDK4/6 inhibitors, LY2835219 and palbociclib, and had better selectivity than LY2835219. Further in vitro study revealed that SPH3643 blocked Cdk/Rb signaling by inhibiting the phosphorylation of RbSer780 and arrested the MCF-7 cancer cells at G0 /G1 phase, resulting in marked inhibition of the proliferation of Rb-positive cancer cell lines. In vivo SPH3643 treatment in mice bearing xenograft tumor models of breast cancer, colon cancer, acute myelocytic leukemia, and glioblastoma resulted in significant decreases in tumor growth. SPH3643 was able to particularly strongly inhibit glioblastoma (U87-MG) cell growth in the brains of orthotopic carcinoma xenograft mice due to its high degree of intracerebral penetration and significant persistence in this setting. Together these results revealed that SPH3643 is a potent, orally active small-molecule inhibitor of CDK4/6 with robust anticancer efficacy and a high degree of blood-brain barrier permeability.


Assuntos
Antineoplásicos/farmacologia , Barreira Hematoencefálica/metabolismo , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Animais , Antineoplásicos/uso terapêutico , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Feminino , Humanos , Células MCF-7 , Camundongos , Camundongos Nus , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/uso terapêutico , Proteína do Retinoblastoma/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Asian Pac J Cancer Prev ; 21(2): 295-300, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32102502

RESUMO

OBJECTIVE: Silica and Benzo(a)pyrene are listed as carcinogens. This study aims to explore Cyclin D1, CDK4 and difference of cell cycle adjusted by MAPK signal transduction pathway in silica and B(a)P-induced malignant transformation of human embryonic lung fibroblasts. METHODS: Activity of the subfamily (ERK, p38 and JNK) of mitogen-activated protein kinase (MAPK), cyclin D1 and CDK4 (cyclin dependent kinase) were evaluated using Human embryonic lung fibroblast (HELF) purchased from the cell room, basic research institute, Chinese Academy of Medical Sciences. The expression of cyclin D1 and CDK4 (cyclin dependent kinase) were measured in silica and B(a)P induced malignant using Western blot (WB) assay. RESULT: P-ERK and P-JNK expression increased significantly (P<0.01), while CDK4 and P-p38 expression decreased (P<0.01, P<0.05) in silica-induced malignant transformation cells compared with the control group. P-ERK, P-JNK and Cyclin D1 expression increased (P<0.01, P<0.01, P<0.05) in B(a)P-induced group compared with the control group. P-ERK and P-JNK expression decreased (P<0.01), while P-p38, Cyclin D1 and CDK4 expression increased (P<0.05, P<0.05, P<0.01) in B(a)P-induced group compared with the silica-induced group. CONCLUSION: MAPK and cyclin D1/CDK4 activation expressed differently in human embryo lung fibroblasts malignant transformation induced by silica and benzopyrene.


Assuntos
Benzopirenos/efeitos adversos , Transformação Celular Neoplásica/patologia , Ciclina D1/metabolismo , Quinase 4 Dependente de Ciclina/metabolismo , Fibroblastos/patologia , Pulmão/patologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Dióxido de Silício/efeitos adversos , Ciclo Celular , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/metabolismo , Células Cultivadas , Ciclina D1/genética , Quinase 4 Dependente de Ciclina/genética , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Pulmão/efeitos dos fármacos , Pulmão/embriologia , Pulmão/metabolismo , Proteínas Quinases Ativadas por Mitógeno/genética , Transdução de Sinais
16.
Eur J Med Chem ; 188: 112032, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31926467

RESUMO

Overexpression and amplification of cyclin-dependent kinase 4/6 (CDK4/6) occur in many cancers and may be the cause of resistance to CDK4/6 inhibitors in preclinical models. However, there are few investigations on the assessment of CDK4/6 expression in tumors or other tissues. Palbociclib, which was approved in 2015 to treat ER+/HER2-breast cancer in combination with letrozole, is a selective CDK4/6 inhibitor. In this study, an intermediate (compound 3), which could be hydrolyzed into the ligand (compound L) consisting of palbociclib as the bioactive molecule and 6-hydrazino nicotinamide (HYNIC) as the bifunctional chelator, was synthesized. Compound L was radiolabeled with 99mTc using tricine/TPPTS or tricine/TPPMS as co-ligands. 99mTc-tricine-TPPTS-L and 99mTc-tricine-TPPMS-L were prepared with high radiochemical purity without postlabeling purification. They had great in vitro stability. Both radiotracers were hydrophilic, but 99mTc-tricine-TPPTS-L had a lower log P value. In vitro cell uptake studies in MCF-7 cells showed that cellular uptake was blocked by preincubation with palbociclib, suggesting a CDK4/6-mediated uptake mechanism. Biodistribution in mice bearing MCF-7 tumors showed that 99mTc-tricine-TPPTS-L had higher tumor uptake than 99mTc-tricine-TPPMS-L, while they had comparable tumor-to-muscle and tumor-to-blood ratios. Radioactivity accumulation in tumors was obvious in micro-SPECT/CT images with 99mTc-tricine-TPPTS-L. When mice were preinjected with palbociclib, tumor uptake of 99mTc-tricine-TPPTS-L significantly decreased and the tumor accumulation was clearly lost, confirming CDK4/6 specificity. All results in this work indicated that 99mTc-tricine-TPPTS-L is a promising tumor imaging agent that targets CDK4/6.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Hidrazinas/química , Niacinamida/análogos & derivados , Compostos de Organotecnécio/química , Piperazinas/química , Piridinas/química , Compostos Radiofarmacêuticos/química , Neoplasias da Mama/metabolismo , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/metabolismo , Relação Dose-Resposta a Droga , Humanos , Hidrazinas/farmacologia , Células MCF-7 , Estrutura Molecular , Niacinamida/química , Niacinamida/farmacologia , Compostos de Organotecnécio/síntese química , Compostos de Organotecnécio/farmacologia , Piperazinas/farmacologia , Piridinas/farmacologia , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacologia , Relação Estrutura-Atividade , Distribuição Tecidual
17.
Mol Med Rep ; 21(2): 649-658, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31974626

RESUMO

Osteosarcoma (OS) is the most common type of primary malignant bone tumor, which has a high incidence rate in children and adolescents. This research aims to reveal the role of long intergenic non­protein coding RNA 00460 (LINC00460) in OS by the loss­of­function experiment. LINC00460 is involved in the development of multiple types of tumor, but the role of LINC00460 in OS is unclear. To discover more effective molecular targets for the treatment of OS, the association between LINC00460 and OS prognosis was analyzed using the Gene Expression Profiling Interactive Analysis database. Additionally, small interfering RNA was used to knockdown LINC00460 gene expression in vitro to verify its biological effects on the viability, invasive and migratory potential of OS cells. LINC00460 knockdown significantly reduced the viability of OS cells and initiated cell cycle arrest within the G0/G1 phase through the decreased expression of cyclin D1 and CDK4/CDK6. In addition, LINC00460 knockdown promoted apoptosis of OS cells, and inhibited the migratory and invasive abilities of OS cells through the inhibition of the epithelial­mesenchymal transition pathway. In conclusion, the present study reported that LINC00460 may predict OS prognosis, and may serve an important role in mediating the viability, invasive and migratory potential of OS cells. Based on these findings, LINC00460 demonstrated promising potential as a future therapeutic target for OS treatment.


Assuntos
Carcinogênese/genética , Osteossarcoma/genética , RNA Longo não Codificante/metabolismo , Apoptose/genética , Carcinogênese/patologia , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Sobrevivência Celular/genética , Ciclina D1/metabolismo , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Transição Epitelial-Mesenquimal/genética , Fase G1/genética , Técnicas de Silenciamento de Genes , Humanos , Metaloproteinase 9 da Matriz/metabolismo , Invasividade Neoplásica , Osteossarcoma/patologia , Prognóstico , RNA Longo não Codificante/genética , RNA Interferente Pequeno/metabolismo , Fase de Repouso do Ciclo Celular/genética
18.
Ir J Med Sci ; 189(3): 825-834, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31900844

RESUMO

AIMS: This study aimed to investigate the effect of long non-coding RNA-plasmacytoma variant translocation 1 (lnc-Pvt1) knockdown on regulating cell proliferation and apoptosis, and to explore its molecular mechanism in multiple myeloma (MM). METHODS: Lnc-Pvt1 expression was detected in MM cell lines (NCI-H929, U-266, LP-1 and RPMI-8226 cell lines) and human normal plasma cells. In U-266 cells and LP-1 cells, control shRNA and lnc-Pvt1 shRNA plasmids were transferred. Rescue experiments were further performed by transfection of lnc-Pvt1 shRNA alone and lnc-Pvt1 shRNA and miR-486 shRNA plasmids. Cells proliferation, apoptosis, RNA expression, and protein expression were determined by cell counting kit-8, annexin V-FITC-propidium iodide, quantitative polymerase chain reaction, and Western blot assays, respectively. RESULTS: Lnc-Pvt1 expression was increased in MM cell lines (NCI-H929, U-266 and LP-1 cell lines) compared with human normal plasma cells. In U-266 cells, lnc-Pvt1 shRNA suppressed cell proliferation while enhanced cell apoptosis compared with control shRNA. Also, lnc-Pvt1 shRNA increased miR-486 expression compared with control shRNA. Further rescue experiment revealed that miR-486 shRNA did not change lnc-Pvt1 level, but increased CDK4 and BCAS2 expressions in lnc-Pvt1 knockdown-treated cells. In addition, miR-486 shRNA promoted cell proliferation while inhibited cell apoptosis in lnc-Pvt1 knockdown-treated cells. These results were further validated in LP-1 cells. CONCLUSIONS: Lnc-Pvt1 knockdown inhibits cell proliferation and induces cell apoptosis through potentially regulating miR-486-mediated CDK4 and BCAS2 in MM.


Assuntos
Quinase 4 Dependente de Ciclina/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Mieloma Múltiplo/genética , Plasmocitoma/genética , RNA Longo não Codificante/genética , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Humanos
19.
Nat Commun ; 11(1): 135, 2020 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-31919362

RESUMO

Functional plasticity of the brain decreases during ageing causing marked deficits in contextual learning, allocentric navigation and episodic memory. Adult neurogenesis is a prime example of hippocampal plasticity promoting the contextualisation of information and dramatically decreases during ageing. We found that a genetically-driven expansion of neural stem cells by overexpression of the cell cycle regulators Cdk4/cyclinD1 compensated the age-related decline in neurogenesis. This triggered an overall inhibitory effect on the trisynaptic hippocampal circuit resulting in a changed profile of CA1 sharp-wave ripples known to underlie memory consolidation. Most importantly, increased neurogenesis rescued the age-related switch from hippocampal to striatal learning strategies by rescuing allocentric navigation and contextual memory. Our study demonstrates that critical aspects of hippocampal function can be reversed in old age, or compensated throughout life, by exploiting the brain's endogenous reserve of neural stem cells.


Assuntos
Hipocampo/fisiologia , Aprendizagem/fisiologia , Consolidação da Memória/fisiologia , Células-Tronco Neurais/fisiologia , Neurogênese/fisiologia , Envelhecimento/fisiologia , Animais , Ciclina D1/metabolismo , Quinase 4 Dependente de Ciclina/metabolismo , Feminino , Memória/fisiologia , Camundongos , Camundongos Endogâmicos C57BL
20.
Lancet Oncol ; 21(2): 250-260, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31859246

RESUMO

BACKGROUND: Cyclin-dependent kinase 4/6 inhibitors (CDKIs) are indicated with endocrine therapy as first-line or second-line treatment for hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer. We aimed to investigate the benefit of adding CDKIs to endocrine therapy in patients whose tumours might have differing degrees of endocrine sensitivity. METHODS: We pooled individual patient data from all phase 3 randomised breast cancer trials of CDKIs plus endocrine therapy submitted to the US Food and Drug Administration before Jan 1, 2019, in support of marketing applications. Our pooled analysis included all randomly assigned patients in these trials who received at least one dose of CDKI or placebo with endocrine therapy (an aromatase inhibitor [letrozole or anastrazole] or fulvestrant). We did prespecified subgroup analyses in patients with progesterone receptor-negative disease; patients with a disease-free interval of 12 months or less; patients with de-novo metastases, lobular histology, and bone-only disease; patients with visceral metastases; and patients aged up to 40 years. Patients who were not treated, who received tamoxifen as endocrine therapy, or who were treated with an aromatase inhibitor but who had received previous chemotherapy in the metastatic setting (not first-line) were excluded from our pooled analyses. All studies had a primary endpoint of investigator-assessed progression-free survival, defined as time from date of randomisation to the initial date of documented cancer progression or death, whichever occurred first. Median progression-free survival was estimated with Kaplan-Meier methods. Hazard ratios (HR) with 95% CIs for progression-free survival were estimated by means of Cox regression models. FINDINGS: The seven studies meeting this study's inclusion criteria were done between Feb 22, 2013, and Nov 3, 2017, with a median duration of follow-up of 19·7 months (IQR 15·9-25·9). 4200 patients were included in the pooled analysis, of whom 1320 received an aromatase inhibitor plus a CDKI, 932 received placebo plus an aromatase inhibitor, 1296 received fulvestrant plus a CDKI, and 652 received fulvestrant plus placebo. Across all seven pooled trials, the difference in estimated median progression-free survival was 8·8 months in favour of CDKI plus endocrine therapy over placebo plus endocrine therapy (range across the trials 6·8-13·3 months; HR 0·59, 95% CI 0·54-0·64). Progression-free survival results favoured the CDKI group in all prespecified clinicopathological subgroups analysed, with similar HRs to that for the broader intended-use population. In first-line aromatase inhibitor-treated patients (n=2252), the median progression-free survival in the CDKI plus aromatase inhibitor group was 28·0 months (95% CI 25·3-29·1) versus 14·9 months (14·0-16·7) in the placebo plus aromatase inhibitor group (difference 13·1 months; range across the trials 13·0-13·3 months; HR 0·55, 95% CI 0·49-0·62). In first-line fulvestrant-treated patients (n=396), the median progression-free survival was 18·6 months (95% CI 14·8-23·5) in the placebo plus fulvestrant group and not estimable (22·4 to not estimable) in the CDKI plus fulvestrant group (difference not estimable; HR 0·58, 95% CI 0·42-0·80). In the patients treated with fulvestrant in the second-line setting and beyond (n=1552), the difference in estimated median progression-free survival between the CDKI plus fulvestrant group and the placebo plus fulvestrant group was 6·9 months in favour of the CDKI group (range across the trials 5·5-7·3 months; HR 0·56, 95% CI 0·49-0·64). INTERPRETATION: Since the addition of CDKI to endocrine therapy seemed to benefit all clinicopathological subgroups of interest in this pooled analysis, further research is needed to identify patient subgroups for whom endocrine therapy alone might be appropriate for first-line or second-line treatment of hormone receptor-positive, HER2-negative metastatic breast cancer. FUNDING: None.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Inibidores da Aromatase/administração & dosagem , Biomarcadores Tumorais/análise , Neoplasias da Mama/tratamento farmacológico , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Inibidores de Proteínas Quinases/administração & dosagem , Receptor ErbB-2/análise , Receptores Estrogênicos/análise , Receptores de Progesterona/análise , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/química , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Ensaios Clínicos Fase III como Assunto , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Aprovação de Drogas , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Transdução de Sinais , Fatores de Tempo , Estados Unidos , United States Food and Drug Administration
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