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1.
Medicine (Baltimore) ; 99(40): e22544, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33019464

RESUMO

BACKGROUND: Clinical studies have shown that celecoxib can significantly inhibit the development of tumors, and basic experiments and in vitro experiments also provide a certain basis, but it is not clear how celecoxib inhibits tumor development in detail. METHODS: A literature search of all major academic databases was conducted (PubMed, China National Knowledge Internet (CNKI), Wan-fang, China Science and Technology Journal Database (VIP), including the main research on the mechanisms of celecoxib on tumors. RESULTS: Celecoxib can intervene in tumor development and reduce the formation of drug resistance through multiple molecular mechanisms. CONCLUSION: Celecoxib mainly regulates the proliferation, migration, and invasion of tumor cells by inhibiting the cyclooxygenases-2/prostaglandin E2 signal axis and thereby inhibiting the phosphorylation of nuclear factor-κ-gene binding, Akt, signal transducer and activator of transcription and the expression of matrix metalloproteinase 2 and matrix metalloproteinase 9. Meanwhile, it was found that celecoxib could promote the apoptosis of tumor cells by enhancing mitochondrial oxidation, activating mitochondrial apoptosis process, promoting endoplasmic reticulum stress process, and autophagy. Celecoxib can also reduce the occurrence of drug resistance by increasing the sensitivity of cancer cells to chemotherapy drugs.


Assuntos
Celecoxib/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Celecoxib/efeitos adversos , Celecoxib/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Dinoprostona/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Metaloproteinase 2 da Matriz/efeitos dos fármacos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/efeitos dos fármacos , Metaloproteinase 9 da Matriz/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos
2.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 45(7): 874-880, 2020 Jul 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-32879093

RESUMO

Chronic myeloid leukemia (CML) is one of the most common hematological malignancies and characterized by the formation of Philadelphia (Ph) chromosome. Recently, tyrosine kinase inhibitors (TKI) treatment greatly improved the prognosis of CML. However, the options may be limited when a patient develops traditional TKI resistance or gene mutation. Herein, we reported a case. A 38-year-old male CML patient developed a BCR-ABL1 gene mutation of T315I after 2.5 years of TKI treatment, including imatinib and dasatinib. We adjusted the treatment with the combined application of dasatinib and axitinib. BCR-ABL1 gene copies dropped down and achieved an early molecular response at 2 months later. Subsequently, he received hematopoietic stem cell transplantation. Axitinib and dasatinib were applied for another half year after the allogeneic hematopoietic stem cell transplantation (allo-HSCT). Two years after the allo-HSCT, the BCR-ABL1 gene was still undetectable. It provided a successful example in treating CML patients carrying BCR-ABL1 T315I mutation via combination of axitinib with conditional TKI.


Assuntos
Axitinibe , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Adulto , Dasatinibe/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Masculino , Mutação , Inibidores de Proteínas Quinases/uso terapêutico
3.
Nat Commun ; 11(1): 4684, 2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32943635

RESUMO

Cancer cells have a characteristic metabolism, mostly caused by alterations in signal transduction networks rather than mutations in metabolic enzymes. For metabolic drugs to be cancer-selective, signaling alterations need to be identified that confer a druggable vulnerability. Here, we demonstrate that many tumor cells with an acquired cancer drug resistance exhibit increased sensitivity to mechanistically distinct inhibitors of cancer metabolism. We demonstrate that this metabolic vulnerability is driven by mTORC1, which promotes resistance to chemotherapy and targeted cancer drugs, but simultaneously suppresses autophagy. We show that autophagy is essential for tumor cells to cope with therapeutic perturbation of metabolism and that mTORC1-mediated suppression of autophagy is required and sufficient for generating a metabolic vulnerability leading to energy crisis and apoptosis. Our study links mTOR-induced cancer drug resistance to autophagy defects as a cause of a metabolic liability and opens a therapeutic window for the treatment of otherwise therapy-refractory tumor patients.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Animais , Apoptose/efeitos dos fármacos , Autofagia/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Desoxiglucose , Tratamento Farmacológico , Feminino , Humanos , Neoplasias Pulmonares , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Anticancer Res ; 40(10): 5509-5516, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988874

RESUMO

BACKGROUND/AIM: Extracellular vesicles (EVs) can mediate drug resistance within the tumor microenvironment by delivering bioactive molecules, including proteins. Here, we performed a comparative proteomic analysis of EVs secreted by A549 lung cancer cells and their cisplatin-resistant counterparts in order to identify proteins involved in drug resistance. MATERIALS AND METHODS: Cells were co-cultivated using a transwell system to evaluate EV exchange. EVs were isolated by ultracentrifugation and analyzed using microscopy and nanoparticle tracking. EV proteome was analyzed by mass spectrometry. RESULTS: EV-mediated communication was observed between co-cultured A549 and A549/CDDP cells. EVs isolated from both cells were mainly exosome-like structures. Extracellular matrix components, cell adhesion proteins, complement factors, histones, proteasome subunits and membrane transporters were found enriched in the EVs released by cisplatin-resistant cells. CONCLUSION: Proteins identified in this work may have a relevant role in modulating the chemosensitivity of the recipient cells and could represent useful biomarkers to monitor cisplatin response in lung cancer.


Assuntos
Biomarcadores Tumorais/genética , Cisplatino/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Proteoma/genética , Células A549 , Cisplatino/efeitos adversos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Exossomos/efeitos dos fármacos , Exossomos/genética , Vesículas Extracelulares/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Espectrometria de Massas , Proteômica/métodos , Microambiente Tumoral/efeitos dos fármacos
5.
Anticancer Res ; 40(10): 5529-5538, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988876

RESUMO

BACKGROUND/AIM: Triple-negative breast cancer (TNBC) is a unique subtype that lacks expression of several conventional biomarkers and has a higher incidence of lymph node invasion and distal metastasis among all breast cancers. Anoikis resistance is the fundamental reason behind tumor cells' survival without their attachment to the extracellular matrix and metastasis to distal organs. Therefore, finding novel anti-cancer drugs that can suppress anoikis resistance in cancer cells is critical for patients with TNBC. MATERIALS AND METHODS: Curcumol, a natural compound, was used to assess whether it can inhibit the anoikis resistance and affects cell mortality and motility of IV2-1 TNBC cells. RESULTS: Curcumol suppressed anoikis resistance and inhibited TNBC cell survival in suspension. Additionally, these anti-cancer effects induced by curcumol could be related to the YAP1/Skp2 molecular pathway. CONCLUSION: Curcumol is an effective Skp2-targeted therapy that attenuates anoikis resistance and metastasis in TNBC cells.


Assuntos
MicroRNAs/genética , Proteínas Quinases Associadas a Fase S/genética , Sesquiterpenos/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Anoikis/efeitos dos fármacos , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Metástase Neoplásica , Transdução de Sinais/efeitos dos fármacos , Transcrição Genética/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
6.
Anticancer Res ; 40(10): 5611-5620, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988885

RESUMO

BACKGROUND/AIM: Cancer stem cell characteristics and drug resistance of colorectal cancer are associated with failure of cancer treatment. In this study, we investigated the effects of PrPC on cancer stem cell characteristics, migration, invasion, and drug resistance of 5FU-resistant CRC cells. MATERIALS AND METHODS: PrPC negative and PrPC positive cells were isolated from 5FU-resistant CRC cells using magnetic activated cell sorting. Sphere formation, cancer stem cell marker expression, migration, invasion, and drug resistance were analyzed. RESULTS: PrPC positive cells showed increased sphere formation capacity and increased expression of cancer stem cell markers compared to PrPC negative cells. In addition, PrPC positive cells showed increased migration, invasion and drug resistance compared to PrPC negative cells. Furthermore, knockdown of PrPC abolished these effects. CONCLUSION: PrPC expression is important in CRC cell behavior, such as sphere formation, migration, invasion, and drug resistance. PrPC is an important therapeutic target for the treatment of CRC.


Assuntos
Neoplasias do Colo/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fluoruracila/farmacologia , Proteínas Priônicas/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/genética , Colo/patologia , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Esferoides Celulares/efeitos dos fármacos
7.
Nat Commun ; 11(1): 4840, 2020 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-32973129

RESUMO

Immunotherapies revolutionized cancer treatment by harnessing the immune system to target cancer cells. However, most patients are resistant to immunotherapies and the mechanisms underlying this resistant is still poorly understood. Here, we report that overexpression of BMP7, a member of the TGFB superfamily, represents a mechanism for resistance to anti-PD1 therapy in preclinical models and in patients with disease progression while on immunotherapies. BMP7 secreted by tumor cells acts on macrophages and CD4+ T cells in the tumor microenvironment, inhibiting MAPK14 expression and impairing pro-inflammatory responses. Knockdown of BMP7 or its neutralization via follistatin in combination with anti-PD1 re-sensitizes resistant tumors to immunotherapies. Thus, we identify the BMP7 signaling pathway as a potential immunotherapeutic target in cancer.


Assuntos
Proteína Morfogenética Óssea 7/genética , Proteína Morfogenética Óssea 7/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Imunoterapia/métodos , Neoplasias/metabolismo , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Linfócitos T CD4-Positivos , Linhagem Celular Tumoral , Feminino , Folistatina/metabolismo , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Proteína Quinase 14 Ativada por Mitógeno/genética , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Receptor de Morte Celular Programada 1/efeitos dos fármacos , Células RAW 264.7 , Proteína Smad1/metabolismo , Transcriptoma , Microambiente Tumoral/efeitos dos fármacos
8.
Anticancer Res ; 40(9): 5091-5095, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878797

RESUMO

BACKGROUND/AIM: The purpose of the present study was to clarify whether treatment with YM155, a novel small-molecule inhibitor of survivin, reversed cabazitaxel resistance in castration-resistant prostate cancer (CRPC). MATERIALS AND METHODS: Cabazitaxel resistance was induced in the castration-resistant prostate cancer cell line, 22Rv1-CR. In vitro and in vivo models were used to test the efficacy of YM155 and cabazitaxel. RESULTS: Survivin gene expression was significantly higher in 22Rv1-CR than its parent cells (22Rv1). In 22Rv1-CR cells, YM155 significantly reduced expression of the survivin gene in a concentration-dependent manner. YM155 alone was poorly effective; however, it significantly enhanced the anticancer effects of cabazitaxel on 22Rv1-CR in vitro and in vivo. CONCLUSION: Inhibition of survivin by YM155 overcomes cabazitaxel resistance in CRPC cells.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Imidazóis/farmacologia , Naftoquinonas/farmacologia , Neoplasias de Próstata Resistentes à Castração/genética , Survivina/genética , Taxoides/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , RNA Mensageiro/genética , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Anticancer Res ; 40(9): 5159-5170, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878804

RESUMO

BACKGROUND/AIM: The aim of this study was to elucidate the possibility of sensitizing colon cancer cells to the chemotherapeutic drug SN38 and investigate its mechanism of action after combined treatment with electroporation (EP). MATERIALS AND METHODS: Cells were treated with SN38, EP and their combination for 24/48 h. The cell viability, actin cytoskeleton integrity, mitochondrial superoxide, hydroperoxides, total glutathione, phosphatidyl serine expression, DNA damages and expression of membrane ABC transporters were analyzed using conventional analytical tests. RESULTS: The combination of EP and SN38 affected cell viability and cytoskeleton integrity. This effect was accompanied by: (i) high production of intracellular superoxide and hydroperoxides and depletion of glutathione; (ii) increased DNA damage and apoptotic/ferroptotic cell death; (iii) changes in the expression of membrane ABC transporters - up-regulation of SLCO1B1 and retention of SN38 in the cells. CONCLUSION: The anticancer effect of the combined treatment of SN38 and EP is related to changes in the redox-homeostasis of cancer cells, leading to cell death via apoptosis and/or ferroptosis. Thus, electroporation has a potential to increase the sensitivity of cancer cells to conventional anticancer therapy with SN38.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Oxirredução , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Dano ao DNA/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Sinergismo Farmacológico , Imunofluorescência , Glutationa/metabolismo , Humanos , Modelos Biológicos , Espécies Reativas de Oxigênio/metabolismo
10.
Anticancer Res ; 40(9): 5309-5311, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878822

RESUMO

BACKGROUND/AIM: Experimental studies have shown that celecoxib is related to the downregulation of Tregs and an increase in the therapeutic efficacy of PD-1 inhibitors; however, such effect has not been shown in human cancers. Our report confirmed the synergistic effect of celecoxib with a PD-1 inhibitor. CASE REPORT: A 57-year-old male with advanced pulmonary adenocarcinoma was treated with nivolumab monotherapy as 5th line sequential treatment. Although the patient experienced tumor remission, regrowth of the primary tumor was observed and he complained of lumbar pain. Therefore, celecoxib (400 mg/day) was initiated without cessation of nivolumab. Chest radiography revealed a marked shrinkage of the primary site, with a decreasing trend of carcinoma embryonic antigen. CONCLUSION: This is the report of a case of recovery of sensitivity to nivolumab by additional treatment with celecoxib.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Celecoxib/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Biomarcadores Tumorais , Celecoxib/administração & dosagem , Celecoxib/efeitos adversos , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Sinergismo Farmacológico , Receptores ErbB/genética , Humanos , Imunomodulação/efeitos dos fármacos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/etiologia , Masculino , Pessoa de Meia-Idade , Mutação , Radiografia Torácica , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Resultado do Tratamento
11.
Anticancer Res ; 40(9): 4829-4841, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878771

RESUMO

Most breast cancers express the estrogen receptor (ER) receptor and are negative for the human epidermal growth factor receptor 2 (HER2) receptor. ER+/HER2- cancers are treated with hormone-based therapies in the adjuvant setting and derive significant survival benefit from these therapies in the metastatic setting. However, hormone resistance develops in most metastatic patients. An increased understanding of the biology of ER+/HER2- breast cancers has led to the development of new therapies for this disease including CDK4/6 inhibitors and PI3K inhibitors. Several other neoplastic processes are targeted by novel drugs in clinical development, addressing cancer vulnerabilities. These include newer ways to block the ER and targeting the HER2 receptors in ER+/HER2- cancers expressing HER2 in low levels not qualifying for clinical positivity. In addition, promising therapeutic options include targeting other surface receptors or their downstream pathways, as well as targeting the apoptotic machinery and boosting the immune response which is initially insufficient in these cancers. A selection of new drugs in advanced development for ER+/HER2- breast cancer will be discussed in this review.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Mutação , Fosfatidilinositol 3-Quinases/metabolismo , Receptor ErbB-2/antagonistas & inibidores , Receptores Estrogênicos/antagonistas & inibidores , Receptores Estrogênicos/genética , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais/efeitos dos fármacos
12.
Anticancer Res ; 40(9): 4921-4928, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878780

RESUMO

BACKGROUND/AIM: Phenothiazines constitute a versatile family of compounds in terms of biological activity, which have also gained a considerable attention in cancer research. MATERIALS AND METHODS: Three phenothiazines (promethazine, chlorpromazine and thioridazine) have been tested in combination with 11 active selenocompounds against MDR (ABCB1-overexpressing) mouse T-lymphoma cells to investigate their activity as combination chemotherapy and as antitumor adjuvants in vitro with a checkerboard combination assay. RESULTS: Seven selenocompounds showed toxicity on mouse embryonic fibroblasts, while three showed selectivity towards tumor cells. Two compounds showed synergism with all tested phenothiazines in low concentration ranges (1.46-11.25 µM). Thioridazine was the most potent among the three phenothiazines. CONCLUSION: Phenothiazines belonging to different generations showed different levels of adjuvant activities. All the tested phenothiazines are already approved medicines with known pharmacological and toxicity profiles, therefore, their use as adjuvants in cancer may be considered as a potential drug repurposing strategy.


Assuntos
Antineoplásicos/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Compostos Organosselênicos/farmacologia , Fenotiazinas/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos/genética , Sinergismo Farmacológico , Linfoma de Células T/tratamento farmacológico , Linfoma de Células T/patologia , Camundongos , Estrutura Molecular , Compostos Organosselênicos/síntese química , Compostos Organosselênicos/química , Fenotiazinas/síntese química , Fenotiazinas/química
13.
Yonsei Med J ; 61(9): 762-773, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32882760

RESUMO

PURPOSE: Pharmacological inhibition of mutant isocitrate dehydrogenase (IDH) reduces R-2-hydroxyglutarate (2-HG) levels and restores cellular differentiation in vivo and in vitro. The IDH2 inhibitor enasidenib (AG-221) has been approved by the FDA as a first-in-class inhibitor for the treatment of relapsed or refractory (R/R) IDH2-mutant acute myeloid leukemia (AML). In this study, the effects of a combination of all-trans retinoic acid (ATRA) and AG-221 on AML cell differentiation was explored, along with the mechanisms employed by IDH2-mutant cells in AML. MATERIALS AND METHODS: We treated the human AML cell line, IDH2-mutant-TF-1, and primary human AML cells carrying IDH2 mutation with 30 µM AG-221 and 100 nM ATRA, alone or in combination. RESULTS: Combined treatment with AG-221 and ATRA inhibited 2-HG production and resulted in synergistic effects on differentiation among IDH2-mutant AML cells and primary AML cells expressing IDH2 mutation. Combined treatment with AG-221 and ATRA altered autophagic activity. AG-221 and ATRA treatment-induced differentiation of IDH2-mutant AML cells was associated with autophagy induction, without suppressing autophagy flux at maturation and degradation stages. A RAF-1/MEK/ERK pathway was founded to be associated with AG-221 and ATRA-induced differentiation in IDH2-mutant AML cells. IDH-associated changes in histone methylation markers decreased after AG-221 and ATRA combination treatment. CONCLUSION: Our preliminary evidence indicates that the addition of ATRA to treatments with IDH2 inhibitor may lead to further improvements or increases in response rates in IDH2-mutant AML patients who do not appear to benefit from treatments with IDH2 inhibitor alone.


Assuntos
Aminopiridinas/farmacologia , Antineoplásicos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Tretinoína/farmacologia , Triazinas/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Isocitrato Desidrogenase/antagonistas & inibidores , Isocitrato Desidrogenase/metabolismo , Leucemia Mieloide Aguda/genética , Mutação
14.
Nat Commun ; 11(1): 4545, 2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32917858

RESUMO

TGF-ß1, ß2 and ß3 bind a common receptor to exert vastly diverse effects in cancer, supporting either tumor progression by favoring metastases and inhibiting anti-tumor immunity, or tumor suppression by inhibiting malignant cell proliferation. Global TGF-ß inhibition thus bears the risk of undesired tumor-promoting effects. We show that selective blockade of TGF-ß1 production by Tregs with antibodies against GARP:TGF-ß1 complexes induces regressions of mouse tumors otherwise resistant to anti-PD-1 immunotherapy. Effects of combined GARP:TGF-ß1/PD-1 blockade are immune-mediated, do not require FcγR-dependent functions and increase effector functions of anti-tumor CD8+ T cells without augmenting immune cell infiltration or depleting Tregs within tumors. We find GARP-expressing Tregs and evidence that they produce TGF-ß1 in one third of human melanoma metastases. Our results suggest that anti-GARP:TGF-ß1 mAbs, by selectively blocking a single TGF-ß isoform emanating from a restricted cellular source exerting tumor-promoting activity, may overcome resistance to PD-1/PD-L1 blockade in patients with cancer.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas de Membrana/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Fator de Crescimento Transformador beta1/antagonistas & inibidores , Animais , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral/transplante , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/imunologia , Células HEK293 , Humanos , Proteínas de Membrana/metabolismo , Camundongos , Neoplasias/imunologia , Neoplasias/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
15.
Nat Commun ; 11(1): 3978, 2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32770044

RESUMO

Methionine restriction, a dietary regimen that protects against metabolic diseases and aging, represses cancer growth and improves cancer therapy. However, the response of different cancer cells to this nutritional manipulation is highly variable, and the molecular determinants of this heterogeneity remain poorly understood. Here we report that hepatocyte nuclear factor 4α (HNF4α) dictates the sensitivity of liver cancer to methionine restriction. We show that hepatic sulfur amino acid (SAA) metabolism is under transcriptional control of HNF4α. Knocking down HNF4α or SAA enzymes in HNF4α-positive epithelial liver cancer lines impairs SAA metabolism, increases resistance to methionine restriction or sorafenib, promotes epithelial-mesenchymal transition, and induces cell migration. Conversely, genetic or metabolic restoration of the transsulfuration pathway in SAA metabolism significantly alleviates the outcomes induced by HNF4α deficiency in liver cancer cells. Our study identifies HNF4α as a regulator of hepatic SAA metabolism that regulates the sensitivity of liver cancer to methionine restriction.


Assuntos
Fator 4 Nuclear de Hepatócito/metabolismo , Neoplasias Hepáticas/metabolismo , Metionina/metabolismo , Animais , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Cisteína/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Fator 4 Nuclear de Hepatócito/genética , Fígado/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Mesoderma/efeitos dos fármacos , Mesoderma/patologia , Redes e Vias Metabólicas/efeitos dos fármacos , Metaboloma/efeitos dos fármacos , Camundongos , Sorafenibe/farmacologia , Transcrição Genética/efeitos dos fármacos
16.
Ecotoxicol Environ Saf ; 202: 110940, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32800223

RESUMO

Recent evidence indicates that chronic, low-dose exposure to mixtures of pesticides can cause adverse responses in a variety of cells, tissues and organs, although interactions between pesticides circulating in the blood and cancer cells remain largely unexplored. The aim of this study was to investigate the potential of a mixture of four pesticides to induce multidrug resistance against the chemotherapeutic agents cisplatin, 5-fluorouracil and temozolomide in the human U87 glioblastoma cell line, and to explore the molecular mechanisms underlying this resistance. We found that the repeated administration of the pesticide mixture (containing the insecticides chlorpyrifos-ethyl and deltamethrin, the fungicide metiram, and the herbicide glyphosate) induced a strong drug resistance in U87 cells. The resistance was durable and transferred to subsequent cell generations. In addition, we detected a significant over-expression of the ATP-binding cassette (ABC) membrane transporters P-gp/ABCB1 and BRCP/ABCG2 as well as a glutathione-S-transferase (GST)/M1-type cellular detoxification function, known to have important roles in multidrug resistance, thus providing molecular support for the acquired multidrug resistance phenotype and shedding light on the mechanism of resistance. We further determined that there was lower mortality in the resistant brain tumor cells and that the mitochondrial apoptosis pathway was activated at a lower rate after chemotherapy compared to non-resistant control cells. In addition, multidrug-resistant cells were found to have both higher motility and wound-healing properties, suggesting a greater metastatic potential. Our results suggest that the investigation of P-gp, BRCP and GST/M1 multidrug resistance gene expression and/or protein levels in biopsy specimens of brain tumor patients who were at risk of pesticide exposure could be beneficial in determining chemotherapy dose and prolonging patient survival.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Praguicidas/toxicidade , Testes de Toxicidade Crônica , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cisplatino , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos/genética , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/farmacologia
17.
Int J Nanomedicine ; 15: 4793-4810, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764921

RESUMO

Background: Platinum resistance is a major challenge in the management of ovarian cancer. Even low levels of acquired resistance at the cellular level lead to impaired response to cisplatin. In ovarian cancer intraperitoneal therapy, nanoparticle formulation can improve the cisplatin's pharmacokinetics and safety profile. Purpose: This work aimed to investigate the chemo-sensitivity of ovarian cancer SKOV3 cells upon short-term (72h) single treatment of cisplatin and cisplatin-loaded biodegradable nanoparticles (Cis-NP). The aim was then to determine the therapeutic properties of Cis-NP in vivo using a SKOV3-luc cells' xenograft model in mice. Methods: Cell cytotoxicity was assessed after the exposure of the cell culture to cisplatin or Cis-NP. The effect of treatments on EMT and CSC-like phenotype was studied by analyzing a panel of markers by flow cytometry. Intracellular platinum concentration was determined by inductively coupled plasma mass spectrometry (ICS-MS), and gene expression was evaluated by RNAseq analysis. The efficacy of intraperitoneal chemotherapy was evaluated in a SKOV3-luc cells' xenograft model in mice, through a combination of bioluminescence imaging, histological, and immunohistochemical analyses. Results: We observed in vitro that short-term treatment of cisplatin has a critical role in determining the potential induction of chemoresistance, and a nanotechnology-based drug delivery system can modulate it. The RNAseq analysis underlines a protective effect of nanoparticle system according to their ability to down-regulate several genes involved in chemoresistance, cell proliferation, and apoptosis. The highest intracellular platinum concentration obtained with Cis-NP treatment significantly improved the efficacy. Consistent with in vitro results, we found that Cis-NP treatment in vivo can significantly reduce tumor burden and aggressiveness compared to the free drug. Conclusion: Nanoparticle-mediated cisplatin delivery may serve as an intracellular depot impacting the cisplatin pharmacodynamic performance at cellular levels. These features may contribute to improving the drawbacks of conventional intraperitoneal therapy, and therefore will require further investigations in vivo.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Portadores de Fármacos/química , Espaço Intracelular/metabolismo , Nanomedicina/métodos , Nanopartículas/química , Neoplasias Ovarianas/tratamento farmacológico , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/química , Cisplatino/metabolismo , Cisplatino/uso terapêutico , Regulação para Baixo/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Yakugaku Zasshi ; 140(8): 963-968, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32741869

RESUMO

Metabolome analysis is an approach to investigate cell characteristics from the metabolites that are constantly produced and changed by those cells. We conducted a metabolome analysis of the response of 786-O renal cell carcinoma (RCC) cells to histone deacetylase (HDAC) inhibitors, which are expected to increase anticancer drug sensitivity, and compared the response with that of drug-resistant cells. Trichostatin A (TSA), an HDAC inhibitor, increased the sensitivity of 786-O cells to sunitinib. Moreover, TCA cycle and nucleotide metabolism of the cells were promoted. The findings that acetylated p53 (active form) and early apoptotic cells were increased suggests that the mechanism involved enhancement of mitochondrial metabolism and function. In addition, established sunitinib-resistant RCC cells were exposed to a combination of sunitinib and TSA, resulting in significant growth inhibition. Principal component analysis revealed that the parent and resistant cells were obviously different, but approximately half their fluctuations were illustrated by the same pathways. In summary, it was suggested that TSA reduced sunitinib resistance by triggering intracellular metabolome shifts in energy metabolism. This was the first recognized mechanism of action of TSA as an HDAC inhibitor.


Assuntos
Antineoplásicos/farmacologia , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Metaboloma , Metabolômica , Sunitinibe/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Humanos , Mitocôndrias/metabolismo , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/metabolismo
19.
Life Sci ; 258: 118186, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32768586

RESUMO

Antioxidants are essential in preventing the formation and suppressing the activities of reactive nitrogen and oxygen species. The aim of this study was to review the role of antioxidants in cancer development or prevention. Antioxidants are believed to prevent and treat various types of malignancies. Currently, natural antioxidant compounds have been generally consumed to prevent and treat cancers. Certainly, phenolic compounds extracted from medicinal plants have opened a new prospect with respect to the prevention and treatment of cancers due to having antioxidant characteristics. However, some recently published studies have revealed that antioxidant compounds do not indicate absolute anti-tumor properties. Some antioxidants are helpful in cancer initiation and progression. Taken together, antioxidants demonstrate a two-faced nature toward cancer. However, it is required to conduct further cell culture and in vivo studies to confirm the exact role of antioxidants and then use them for efficient cancer treatments.


Assuntos
Antioxidantes/uso terapêutico , Neoplasias/tratamento farmacológico , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Carcinogênese/efeitos dos fármacos , Carcinogênese/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Metástase Neoplásica , Neoplasias/patologia
20.
Int J Nanomedicine ; 15: 5445-5458, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801699

RESUMO

5-Fluorouracil (5-FU) has become one of the most widely employed antimetabolite chemotherapeutic agents in recent decades. It is considered a first line antineoplastic agent for the treatment of colorectal cancer. Unfortunately, chemotherapy with 5-FU has several limitations, including its short half-life, high cytotoxicity and low bioavailability. In order to overcome the drawbacks of 5-FU and enhance its therapeutic efficiency, many scientific groups have focused on designing a new delivery system to successfully deliver 5-FU to tumor sites. We provide a comprehensive review on different strategies to design effective delivery systems, including nanoformulations, drug-conjugate formulations and other strategies for the delivery of 5-FU to colorectal cancer. Furthermore, co-delivery of 5-FU with other therapeutics is discussed. This review critically highlights the recent innovations in and literature on various types of carrier system for 5-FU.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Fluoruracila/administração & dosagem , Animais , Antimetabólitos Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Disponibilidade Biológica , Portadores de Fármacos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fluoruracila/farmacocinética , Humanos , Nanoestruturas/administração & dosagem , Nanoestruturas/química
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