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1.
Toxicol Lett ; 322: 12-19, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31899212

RESUMO

Benzene exposure is a risk factor of acute myeloid leukemia (AML), during such carcinogenesis long non-coding RNAs (lncRNAs) are important epigenetic regulators. HOTAIRM1 (HOXA transcript antisense RNA, myeloid-specific 1) plays an indispensable role in the development of AML. Hydroquinone (HQ) is one major metabolite of benzene and its ideal replacement in toxicology research. But the influence of benzene or HQ on HOTAIRM1 expression in AML associated pathway is still unclear. In the TK6 cells with short-term exposure to HQ (HQ-ST cells) or long term HQ exposure induced malignant transformed TK6 cells (HQ-MT cells), the relationship between DNMT3b and HOTAIRM1 was explored. Comparing to counterparts, HOTAIRM1 expression was increased firstly and then decreased in HQ-ST cells, and definitely decreased in HQ-MT cells; while the expression change tendency of DNMT3b was in contrast to that of HOTAIRM1. Moreover, the average HOTAIRM1 expression of 17 paired workers being exposed to benzene within 1.5 years was increased, but that of the remaining 92 paired workers with longer exposure time was decreased. Furthermore, in 5-AzaC (DNA methyltransferase inhibitor) or TSA (histone deacetylation inhibitor) treated HQ-MT cells, the expression of HOTAIRM1 was restored by reduced DNA promoter methylation levels. HQ-MT cells with DNMT3b knockout by CRISPR/Cas9 displayed the promoter hypomethylation and the increase of HOTAIRM1, also confirmed in benzene exposure workers. These suggest that long term exposure to HQ or benzene might induce the increase of DNMT3b expression and the promoter hypermethylation to silence the expression of HOTAIRM1, a possible tumor-suppressor in the AML associated carcinogenesis pathway.


Assuntos
Benzeno/efeitos adversos , DNA (Citosina-5-)-Metiltransferases/biossíntese , Metilação de DNA/efeitos dos fármacos , Inativação Gênica/efeitos dos fármacos , Hidroquinonas/toxicidade , Leucemia Mieloide Aguda/induzido quimicamente , MicroRNAs/metabolismo , Doenças Profissionais/induzido quimicamente , Exposição Ocupacional/efeitos adversos , Estudos de Casos e Controles , Linhagem Celular Transformada , Linhagem Celular Tumoral , DNA (Citosina-5-)-Metiltransferases/genética , Indução Enzimática , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/genética , MicroRNAs/genética , Doenças Profissionais/enzimologia , Doenças Profissionais/genética , Regiões Promotoras Genéticas , Medição de Risco
2.
Life Sci ; 243: 117234, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31887299

RESUMO

PURPOSE: In acute myeloid leukemia (AML), complete remission can be achieved in parts of patients using cytarabine/anthracycline combination-based chemotherapy, however, drug resistance-related recurrence is still a common cause of treatment failure, leading to high mortality among patients. In our research, we revealed the molecular mechanisms that were sufficient to improve sensitivity of AML cells to the anthracycline daunorubicin (DNR). METHODS: We evaluated the effects of autophagy and apoptosis induced by DNR using two AML cell lines HL60 and U937.Western blot was preformed to analyze the apoptotic pathway protein expression and flow cytometric analysis was used to detect the level of apoptosis in AML cells. The levels of autophagy-related proteins were detected by western blotting and autophagic vesicles were observed by electron microscopy. RESULTS: DNR effectively induced autophagy in two AML cell lines HL60 and U937 confirming by upregulation of LC3-II lipidation, formation of autophagosomes. Inhibition of autophagy by pharmacologic inhibitor HCQ promoted apoptosis induced by DNR, suggesting that autophagy played a vital role in pro-survival in AML. Furthermore, ULK1 inhibition by a highly selective kinase inhibitor SBI-0206965 and shRNA enhanced cytotoxicity of DNR against AML cells. Independent of mTOR -ULK1 signaling pathway, activation of autophagy of DNR was proved to be mediated by AMPK (pThr172)/ULK1 pathway. CONCLUSIONS: These results revealed that pro-survival autophagy induced by ULK1 activation was one of the potential mechanisms of AML resistance to DNR. Targeting ULK1 selectively could be a promising therapeutic strategy to enhance sensitivity of DNR for AML therapy.


Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/antagonistas & inibidores , Daunorrubicina/uso terapêutico , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Leucemia Mieloide Aguda/tratamento farmacológico , Antibióticos Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Daunorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Inibidores Enzimáticos/farmacologia , Células HL-60 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/patologia , Fosforilação , Células U937
3.
Cancer Metastasis Rev ; 38(4): 829-837, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31802358

RESUMO

Matrix metalloproteinases (MMPs) play a major role in extracellular matrix remodeling and are involved in tumor cell invasion. Cancers such as childhood leukemia are characterized by their capacity to infiltrate different organs. MMP production by leukemic cells may indicate a leukemic subtype or subpopulation with a more invasive phenotype. Therefore, clarifying the action mechanisms of MMPs as prognostic predictors or MMP targeting as a therapeutic strategy is necessary. MMP-targeting drugs have been developed for the treatment of hematological malignancies. In this review, we highlight current advances in understanding the molecular mechanisms and pathological characteristics of various MMPs, as well as recent therapeutic advances targeting MMPs in childhood leukemia. Several studies have been conducted on the therapeutic efficacy of MMP inhibitors in cancer, such as collagen peptidomimetics, nonpeptidomimetic inhibitors of MMP active sites, bisphosphonates, and tetracycline derivatives. Here, we conclude that more clinical trials are necessary to estimate the role of selective MMP inhibitors in the treatment and prevention of childhood leukemia.


Assuntos
Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/terapia , Metaloproteinases da Matriz/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/enzimologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Animais , Criança , Humanos
4.
Nat Struct Mol Biol ; 26(11): 999-1012, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31611688

RESUMO

Protein arginine methyltransferase 5 (PRMT5) has emerged as a promising cancer drug target, and three PRMT5 inhibitors are currently in clinical trials for multiple malignancies. In this study, we investigated the role of PRMT5 in human acute myeloid leukemia (AML). Using an enzymatic dead version of PRMT5 and a PRMT5-specific inhibitor, we demonstrated the requirement of the catalytic activity of PRMT5 for the survival of AML cells. We then identified PRMT5 substrates using multiplexed quantitative proteomics and investigated their role in the survival of AML cells. We found that the function of the splicing regulator SRSF1 relies on its methylation by PRMT5 and that loss of PRMT5 leads to changes in alternative splicing of multiple essential genes. Our study proposes a mechanism for the requirement of PRMT5 for leukemia cell survival and provides potential biomarkers for the treatment response to PRMT5 inhibitors.


Assuntos
Leucemia Mieloide Aguda/enzimologia , Proteínas de Neoplasias/fisiologia , Processamento de Proteína Pós-Traducional , Proteína-Arginina N-Metiltransferases/fisiologia , Processamento de RNA , Animais , Antineoplásicos/farmacologia , Arginina/análogos & derivados , Arginina/biossíntese , Arginina/metabolismo , Catálise , Linhagem Celular Tumoral , Sobrevivência Celular , Inibidores Enzimáticos/farmacologia , Regulação Leucêmica da Expressão Gênica , Humanos , Leucemia Mieloide Aguda/genética , Metilação , Camundongos , Terapia de Alvo Molecular , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Proteínas de Fusão Oncogênica/genética , Processamento de Proteína Pós-Traducional/genética , Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Proteína-Arginina N-Metiltransferases/deficiência , Proteômica , Fatores de Processamento de Serina-Arginina/metabolismo
5.
Best Pract Res Clin Haematol ; 32(2): 154-162, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31203997

RESUMO

FLT3 mutations occur in up to a third of newly diagnosed patients with acute myeloid leukemia (AML) and confer poor prognosis. Clinical development of FLT3 tyrosine kinase inhibitors for AML initially involved broad-spectrum inhibitors (midostaurin, sorafenib) targeting multiple kinases. Addition of midostaurin to upfront intensive chemotherapy for younger patients with FLT3 mutant AML significantly improved overall survival and validated FLT3 as a therapeutic target. Other regimens such as sorafenib and hypomethylating agents (azacitidine, decitabine) have expanded the use of FLT3 inhibitors to other populations with FLT3 mutant AML. However, emerging data on new highly potent and specific FLT3 inhibitors such as quizartinib, gilteritinib, and crenolanib suggest that these agents may soon supplant midostaurin and sorafenib in the upfront setting. Using case presentations, this review provides guidelines and practical management strategies for frontline therapy of patients with newly diagnosed FLT3 mutant AML in the current era.


Assuntos
Leucemia Mieloide Aguda , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Tirosina Quinase 3 Semelhante a fms , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/genética , Guias de Prática Clínica como Assunto , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/metabolismo
7.
Cancer Cell ; 35(4): 677-691.e10, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30991027

RESUMO

FTO, an mRNA N6-methyladenosine (m6A) demethylase, was reported to promote leukemogenesis. Using structure-based rational design, we have developed two promising FTO inhibitors, namely FB23 and FB23-2, which directly bind to FTO and selectively inhibit FTO's m6A demethylase activity. Mimicking FTO depletion, FB23-2 dramatically suppresses proliferation and promotes the differentiation/apoptosis of human acute myeloid leukemia (AML) cell line cells and primary blast AML cells in vitro. Moreover, FB23-2 significantly inhibits the progression of human AML cell lines and primary cells in xeno-transplanted mice. Collectively, our data suggest that FTO is a druggable target and that targeting FTO by small-molecule inhibitors holds potential to treat AML.


Assuntos
Dioxigenase FTO Dependente de alfa-Cetoglutarato/antagonistas & inibidores , Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Dioxigenase FTO Dependente de alfa-Cetoglutarato/química , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Dioxigenase FTO Dependente de alfa-Cetoglutarato/metabolismo , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Humanos , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Metilação , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Terapia de Alvo Molecular , Conformação Proteica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais , Relação Estrutura-Atividade , Células U937 , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Expert Opin Investig Drugs ; 28(4): 337-349, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30775933

RESUMO

INTRODUCTION: Tyrosine kinases (TKs) drive cell survival and proliferation in many normal and malignant cell types. TKs are frequently mutated in acute myeloid leukemia (AML) and hence are increasingly targeted. The management of AML has dramatically improved because of TKI-targeted treatment. AREAS COVERED: This review provides a biological background for TK inhibitors (TKIs) in AML and reviews their use in the clinic. TK expression and mutation in AML are explored with a focus on TKs associated with specific AML subsets and treatment outcomes. TKIs that specifically target FLT3, c-Kit, and Jak2 are discussed. TKI targeting of specific genes mutated in individual cases and general 'untargeted' use of these agents are highlighted. Lastly, the mechanisms TKI drug resistance in AML are explored EXPERT OPINION: The use of TKIs in the clinic is improving outcomes for many patients. An improved understanding of tyrosine kinase biology and the expanding use of TKIs are likely to dramatically improve outcomes in the coming decade. TKIs and other targeted agents could gradually supplant the use of cytotoxic chemotherapy for AML.


Assuntos
Antineoplásicos/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/metabolismo , Leucemia Mieloide Aguda/enzimologia , Terapia de Alvo Molecular , Mutação , Proteínas Proto-Oncogênicas c-kit/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-kit/metabolismo , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/metabolismo
9.
Leuk Res ; 78: 12-20, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30660961

RESUMO

Acute myeloid leukemia (AML) is a heterogeneous group of fast growing cancers of myeloid progenitor cells, for which effective treatments are still lacking. Identification of signaling inhibitors that block their proliferation could reveal the proliferative mechanism of a given leukemia cell, and provide small molecule drugs for targeted therapy for AML. In this study, kinase inhibitors that block the majority of cancer signaling pathways are evaluated for their inhibition of two AML cell lines of the M5 subtypes, CTV-1 and THP-1. While THP-1 cells do not respond to any of these inhibitors, CTV-1 cells are potently inhibited by dasatinib, bosutinib, crizotinib, A-770041, and WH-4-23, all potent inhibitors for Lck, a Src family kinase. CTV-1 cells contain a kinase activity that phosphorylates an Lck-specific peptide substrate in an Lck inhibitor-sensitive manner. Furthermore, the Lck gene is over-expressed in CTV-1, and it contains four mutations, two of which are located in regions critical for Lck negative regulation, and are confirmed to activate Lck. Collectively, these results provide strong evidence that mutated and overexpressed Lck is driving CTV-1 proliferation. While Lck activation and overexpression is rare in AML, this study provides a potential therapeutic strategy for treating patients with a similar oncogenic mechanism.


Assuntos
Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/genética , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Humanos , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/metabolismo
10.
Leukemia ; 33(1): 37-51, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29884901

RESUMO

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy for which new therapeutic approaches are required. One such potential therapeutic strategy is to target the ubiquitin-like modifier-activating enzyme 1 (UBA1), the initiating enzyme in the ubiquitylation cascade in which proteins are tagged with ubiquitin moieties to regulate their degradation or function. Here, we evaluated TAK-243, a first-in-class UBA1 inhibitor, in preclinical models of AML. In AML cell lines and primary AML samples, TAK-243 induced cell death and inhibited clonogenic growth. In contrast, normal hematopoietic progenitor cells were more resistant. TAK-243 preferentially bound to UBA1 over the related E1 enzymes UBA2, UBA3, and UBA6 in intact AML cells. Inhibition of UBA1 with TAK-243 decreased levels of ubiquitylated proteins, increased markers of proteotoxic stress and DNA damage stress. In vivo, TAK-243 reduced leukemic burden and targeted leukemic stem cells without evidence of toxicity. Finally, we selected populations of AML cells resistant to TAK-243 and identified missense mutations in the adenylation domain of UBA1. Thus, our data demonstrate that TAK-243 targets AML cells and stem cells and support a clinical trial of TAK-243 in this patient population. Moreover, we provide insight into potential mechanisms of acquired resistance to UBA1 inhibitors.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Leucemia Mieloide Aguda/tratamento farmacológico , Nucleosídeos/farmacologia , Sulfonamidas/farmacologia , Enzimas Ativadoras de Ubiquitina/antagonistas & inibidores , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Proliferação de Células/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/patologia , Camundongos , Camundongos SCID , Células Tumorais Cultivadas
11.
Leukemia ; 33(4): 931-944, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30291336

RESUMO

Chemoresistance may be due to the survival of leukemia stem cells (LSCs) that are quiescent and not responsive to chemotherapy or lie on the intrinsic or acquired resistance of the specific pool of AML cells. Here, we found, among well-established LSC markers, only CD123 and CD47 are correlated with AML cell chemosensitivities across cell lines and patient samples. Further study reveals that percentages of CD123+CD47+ cells significantly increased in chemoresistant lines compared to parental cell lines. However, stemness signature genes are not significantly increased in resistant cells. Instead, gene changes are enriched in cell cycle and cell survival pathways. This suggests CD123 may serve as a biomarker for chemoresistance, but not stemness of AML cells. We further investigated the role of epigenetic factors in regulating the survival of chemoresistant leukemia cells. Epigenetic drugs, especially histone deacetylase inhibitors (HDACis), effectively induced apoptosis of chemoresistant cells. Furthermore, HDACi Romidepsin largely reversed gene expression profile of resistant cells and efficiently targeted and removed chemoresistant leukemia blasts in xenograft AML mouse model. More interestingly, Romidepsin preferentially targets CD123+ cells, while chemotherapy drug Ara-C mainly targeted fast-growing, CD123- cells. Therefore, Romidepsin alone or in combination with Ara-C may be a potential treatment strategy for chemoresistant patients.


Assuntos
Antígeno CD47/antagonistas & inibidores , Depsipeptídeos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Subunidade alfa de Receptor de Interleucina-3/antagonistas & inibidores , Leucemia Mieloide Aguda/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Animais , Antimetabólitos Antineoplásicos/farmacologia , Apoptose , Ciclo Celular , Citarabina/farmacologia , Humanos , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Fenótipo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Cancer Lett ; 442: 193-201, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30429106

RESUMO

ADAM28 has been shown to relate with tumor proliferation and prognosis. The expression of ADAM28 is up-regulated in acute myeloid leukemia (AML). However, the mechanism by which ADAM28 regulates the leukemic cell and the prognostic relevance with AML remain unknown. Here, we found that the expression level of ADAM28 was significantly elevated in AML patients suffering a relapse compared with those remaining in complete remission (CR). ADAM28 promoted the proliferation, migration and invasion in leukemic cells in vitro. Additionally, the increased expression of ADAM28 led to more IGFBP-3 degradation and IGF-I-induced cell proliferation. In a xenotransplantation mouse model, knockout of ADAM28 alleviated HL-60 cells growth and dissemination. The cumulative incidence of relapse (CIR) was significantly higher in patients with high ADAM28 expression. When separately considering the impact of ADAM28 on prognosis within the risk stratifications, patients with high ADAM28 expression levels had a significantly higher CIR in the favorable and intermediate-risk group but not in poor-risk group. Taken together, these data suggest a pivotal role for ADAM28 in regulating the proliferation and invasion of leukemic cells and in the prediction of relapse in AML patients.


Assuntos
Proteínas ADAM/metabolismo , Movimento Celular , Proliferação de Células , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Leucemia Mieloide Aguda/enzimologia , Proteínas ADAM/genética , Animais , Células HL-60 , Humanos , Células K562 , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Masculino , Camundongos Endogâmicos NOD , Camundongos SCID , Invasividade Neoplásica , Prognóstico , Proteólise , Recidiva , Transdução de Sinais , Células THP-1 , Fatores de Tempo , Carga Tumoral , Células Tumorais Cultivadas
13.
EBioMedicine ; 39: 159-172, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30527624

RESUMO

BACKGROUND: Ubiquitin-proteasome system (UPS) is integral to cell survival by maintaining protein homeostasis, and its dysfunction has been linked to cancer and several other human diseases. Through counteracting ubiquitination, deubiquitinases (DUBs) can either positively or negatively regulate UPS function, thereby representing attractive targets of cancer therapies. Previous studies have shown that metal complexes can inhibit tumor growth through targeting the UPS; however, novel metal complexes with higher specificity for cancer therapy are still lacking. METHODS: We synthesized a new gold(I) complex, Au(PPh3)PT. The inhibitory activity of Au(PPh3)PT on the UPS and the growth of multiple cancer cell types were tested in vitro, ex vivo, and in vivo. Furthermore, we compared the efficacy of Au(PPh3)PT with other metal compounds in inhibition of UPS function and tumor growth. FINDINGS: Here we report that (i) a new gold(I) complex-pyrithione, i.e., Au(PPh3)PT, induced apoptosis in two lung cancer cell lines A549 and NCI-H1299; (ii) Au(PPh3)PT severely impaired UPS proteolytic function; (iii) Au(PPh3)PT selectively inhibited 19S proteasome-associated DUBs (UCHL5 and USP14) and other non-proteasomal DUBs with minimal effects on the function of 20S proteasome; (iv) Au(PPh3)PT induced apoptosis in cancer cells from acute myeloid leukemia patients; (v) Au(PPh3)PT effectively suppressed the growth of lung adenocarcinoma xenografts in nude mice; and (vi) Au (PPh3)PT elicited less cytotoxicity in normal cells than several other metal compounds. INTERPRETATION: Together, this study discovers a new gold(I) complex to be an effective inhibitor of the DUBs and a potential anti-cancer drug. FUND: The National High Technology Research and Development Program of China, the project of Guangdong Province Natural Science Foundation, the projects from Foundation for Higher Education of Guangdong, the project from Guangzhou Medical University for Doctor Scientists, the Medical Scientific Research Foundation of Guangdong Province, and the Guangzhou Key Medical Discipline Construction Project Fund.


Assuntos
Enzimas Desubiquitinantes/antagonistas & inibidores , Inibidores Enzimáticos/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Compostos Organoáuricos/administração & dosagem , Compostos Organofosforados/química , Compostos Organoplatínicos/química , Células A549 , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Regulação Neoplásica da Expressão Gênica , Ouro , Humanos , Leucemia Mieloide Aguda/enzimologia , Neoplasias Pulmonares/enzimologia , Camundongos , Camundongos Nus , Compostos Organoáuricos/química , Compostos Organoáuricos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Yi Chuan ; 40(11): 988-997, 2018 Nov 20.
Artigo em Chinês | MEDLINE | ID: mdl-30465531

RESUMO

Leukemia is a group of hematologic malignancy that has unfavorable prognosis and unclear mechanisms. In recent years, advances in leukemia research encompass the discovery of novel targets in acute myeloid leukemia drug resistance, epigenetic crosstalk in mixed lineage leukemia (MLL) leukemogenesis, genetic mechanisms of aggressive NK-cell leukemia, as well as the critical role of key epigenetic regulator in acute myeloid malignancy. Remarkably, researchers revealed that the histone modifying gene SETD2 as a new tumor suppressor and therapeutic target in patients with acute myeloid leukemia. Furthermore, low-dose chemotherapy as a frontline regiment in treating pediatric acute myeloid leukemia can substantially reduce the toxic side effects and treatment costs without impairing efficacy. Although advances in cancer genomics have greatly increased our understanding of the molecular characteristics in tumor biology, recent studies suggest that Darwinian evolution of intratumor heterogeneity represents a major challenge to develop therapeutic strategies to improve disease control. Researchers also dissected the distinct evolutionary dynamics under different chemotherapy regimens and the corresponding applications in the evaluation of treatment outcomes. Altogether, these efforts offered new opportunities for the development of acute myeloid leukemia diagnostics and therapeutics.


Assuntos
Leucemia Mieloide Aguda/genética , Pesquisa Médica Translacional , Animais , Genômica , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/enzimologia
15.
Best Pract Res Clin Haematol ; 31(4): 337-340, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30466743

RESUMO

The FLT3 inhibitor midostaurin, the antibody-drug conjugate gemtuzumab ozogamicin, CPX-351 (liposomal daunorubicin and cytarabine), and the IDH2 inhibitor enasidenib are among the novel agents approved for use in the clinic this past year. This year, 2018, already has seen the regulatory approval of the BCL2 inhibitor venetoclax in the form of breakthrough designation and the IDH1 inhibitor ivosidenib received full FDA approval. Much remains to be learned about how best to use these drugs to improve patient outcomes and how best to employ and interpret next-generation sequencing to determine measurable residual disease (MRD) levels that can more accurately predict risk of relapse.


Assuntos
Aprovação de Drogas , Sequenciamento de Nucleotídeos em Larga Escala , Isocitrato Desidrogenase , Leucemia Mieloide Aguda , Inibidores de Proteínas Quinases/uso terapêutico , Tirosina Quinase 3 Semelhante a fms , Humanos , Isocitrato Desidrogenase/antagonistas & inibidores , Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/genética , Neoplasia Residual , Estados Unidos , United States Food and Drug Administration , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/genética
16.
Best Pract Res Clin Haematol ; 31(4): 401-404, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30466756

RESUMO

Determining which FLT3 inhibitor holds the greatest promise is a difficult task, as the drugs vary according to potency, specificity, protein-binding, drug interactions, and side effect profile. The best choice depends on when in the course of the disease the inhibitor will be used. Moreover, as the results of ongoing trials become available, newer agents could supplant former 'best' drugs. This paper reviews FLT3 inhibitors in combination with chemotherapy early in the disease in FLT3 mutant patients, as single agents or in combination in advanced disease, or in the post-transplant setting to provide separate answers to the main question.


Assuntos
Leucemia Mieloide Aguda , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Tirosina Quinase 3 Semelhante a fms , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/genética , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/metabolismo
17.
Anticancer Res ; 38(11): 6147-6156, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30396931

RESUMO

BACKGROUND/AIM: MEK inhibitors are new promising anticancer drugs. The aim of this study was to investigate the effect of the combination treatment of voreloxin with the MEK inhibitor TAK-733 on HL60 myeloid leukemia cells. MATERIALS AND METHODS: MAPK activity, cell viability, apoptosis, oxidative stress induction and AIF (apoptosis-inducing factor) distribution were assessed in HL60 cells cultured with each drug alone or with both drugs. RESULTS: TAK-733 alone at 5 µM significantly reduced MAPK activity and did not influence viability and apoptosis in HL60 cells. Voreloxin at concentration of 0.03-0.48 µM reduced cell viability and increased apoptosis rate. Incubation with both drugs caused further inhibition of cell viability and increased apoptosis associated with generation of reactive oxygen species (ROS) and nuclear translocation of AIF. CONCLUSION: Combination of TAK-733 and voreloxin can exert a synergistic anticancer effect in myeloid leukemia cells.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Naftiridinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridonas/farmacologia , Pirimidinonas/farmacologia , Tiazóis/farmacologia , Apoptose/efeitos dos fármacos , Fator de Indução de Apoptose/metabolismo , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Células HL-60 , Humanos , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , MAP Quinase Quinase Quinases/antagonistas & inibidores , MAP Quinase Quinase Quinases/metabolismo , Microscopia Confocal , Naftiridinas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Piridonas/administração & dosagem , Pirimidinonas/administração & dosagem , Espécies Reativas de Oxigênio/metabolismo , Tiazóis/administração & dosagem
19.
Clin Biochem ; 61: 34-39, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30176240

RESUMO

OBJECTIVES: Molecular screening plays a major role in prognostic categorization and subsequent definition of treatment strategies for acute myeloid leukemia. The possibility of using IDH1/2 mutations as a marker for the monitoring of minimal residual disease (MRD) is still under investigation and remains unclear. METHODS: In this retrospective study, we evaluated 90 patients with de novo AML using Sanger sequencing (exon 4, IDH1 and IDH2). For subsequent MRD monitoring were used both methods, massive parallel sequencing and droplet digital PCR (ddPCR). RESULTS: We identified 22 patients (24%) who harboured mutations in IDH1 or IDH2 genes. Fourteen (64%) of them had other commonly used MRD markers (insertion in NPM1 and partial tandem duplication of MLL, MLL-PTD). Eight of the 22 patients had IDH1 mutations, 13 had IDH2 mutations and 1 had both IDH1 and IDH2 mutations. In our cohort, this IDH1/2 marker responded to the treatment in all of the patients and reflected the onset of the relapse very well. NPM1 mutation based MRD monitoring was more sensitive and predicted relapse earlier but IDH1/2 based monitoring was more sensitive than a method based on MLL-PTD. Both massive parallel sequencing and ddPCR were competent to monitor MRD using IDH1/2. Nevertheless, ddPCR was able to achieve a higher sensitivity in some cases and moreover this method can analyse a single sample without significant price increases. CONCLUSION: Given these data, we conclude that IDH1/2 mutations can be used as a reliable and cost-effective marker for MRD monitoring.


Assuntos
Predisposição Genética para Doença , Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/genética , Mutação , Adulto , Idoso , Substituição de Aminoácidos , Estudos de Coortes , República Tcheca , Análise Mutacional de DNA , Éxons , Feminino , Seguimentos , Estudos de Associação Genética , Hospitais Universitários , Humanos , Isocitrato Desidrogenase/química , Isocitrato Desidrogenase/metabolismo , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Neoplasia Residual , Prognóstico , Indução de Remissão , Estudos Retrospectivos
20.
J Med Chem ; 61(17): 7785-7795, 2018 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-30125504

RESUMO

The simultaneous inhibition of polo-like kinase 1 (PLK1) and BRD4 bromodomain by a single molecule could lead to the development of an effective therapeutic strategy for a variety of diseases in which PLK1 and BRD4 are implicated. Compound 23 has been found to be a potent dual kinase-bromodomain inhibitor (BRD4-BD1 IC50 = 28 nM, PLK1 IC50 = 40 nM). Compound 6 was found to be the most selective PLK1 inhibitor over BRD4 in our series (BRD4-BD1 IC50 = 2579 nM, PLK1 IC50 = 9.9 nM). Molecular docking studies with 23 and BRD4-BD1/PLK1 as well as with 6 corroborate the biochemical assay results.


Assuntos
Proteínas de Ciclo Celular/antagonistas & inibidores , Desenho de Drogas , Leucemia Mieloide Aguda/tratamento farmacológico , Proteínas Nucleares/antagonistas & inibidores , Conformação Proteica , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Fatores de Transcrição/antagonistas & inibidores , Humanos , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/patologia , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Domínios Proteicos , Relação Estrutura-Atividade , Células Tumorais Cultivadas
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