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1.
J Clin Invest ; 131(12)2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-34128473

RESUMO

Cancer cells reprogram lipid metabolism during their malignant progression, but limited information is currently available on the involvement of alterations in fatty acid synthesis in cancer development. We herein demonstrate that acetyl-CoA carboxylase 1 (ACC1), a rate-limiting enzyme for fatty acid synthesis, plays a critical role in regulating the growth and differentiation of leukemia-initiating cells. The Trib1-COP1 complex is an E3 ubiquitin ligase that targets C/EBPA, a transcription factor regulating myeloid differentiation, for degradation, and its overexpression specifically induces acute myeloid leukemia (AML). We identified ACC1 as a target of the Trib1-COP1 complex and found that an ACC1 mutant resistant to degradation because of the lack of a Trib1-binding site attenuated complex-driven leukemogenesis. Stable ACC1 protein expression suppressed the growth-promoting activity and increased ROS levels with the consumption of NADPH in a primary bone marrow culture, and delayed the onset of AML with increases in mature myeloid cells in mouse models. ACC1 promoted the terminal differentiation of Trib1-COP1-expressing cells and eradicated leukemia-initiating cells in the early phase of leukemic progression. These results indicate that ACC1 is a natural inhibitor of AML development. The upregulated expression of the ACC1 protein has potential as an effective strategy for cancer therapy.


Assuntos
Acetil-CoA Carboxilase/metabolismo , Ácidos Graxos/biossíntese , Leucemia Mieloide Aguda/enzimologia , Proteínas de Neoplasias/metabolismo , Proteólise , Acetil-CoA Carboxilase/genética , Animais , Estabilidade Enzimática , Ácidos Graxos/genética , Células HEK293 , Células HL-60 , Humanos , Células K562 , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Camundongos , Mutação , Proteínas de Neoplasias/genética , Células THP-1 , Células U937
3.
Aging (Albany NY) ; 13(10): 14088-14108, 2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-33999861

RESUMO

Caspase1 (CASP1) is a gene that encodes multiple proteins related to cell death. Nevertheless, the function of CASP1 in the pathogenesis of AML is still unclear. In the present study, a detailed analysis of cancer versus normal samples was performed to explore the relationship between CASP1 and leukemia. We used sequencing data from multiple cancer gene databases to analyze the gene expression and regulatory network of CASP1 in leukemia. We discovered that mRNA expression levels of CASP1 are increased in leukemia cell lines, especially in acute myelocytic leukemia (AML). Then, we verified the mRNA expression of CASP1 in AML clinical samples and observed significantly higher expression of CASP1 in relapsed AML patients. High CASP1 expression was associated with poor prognosis and CASP1 inhibition could impair the proliferation of AML cells. Related functional network identification suggests that CASP1 regulates apoptosis, immune and inflammatory response via pathways involving LYN, LCK, and the E2F family. These findings suggest that CASP1 probably contributes to the pathogenesis, and identify CASP1 as a factor for predicting the prognosis and as a therapeutic target of AML patients.


Assuntos
Caspase 1/genética , Regulação Leucêmica da Expressão Gênica , Leucemia Mieloide Aguda/genética , Caspase 1/metabolismo , Inibidores de Caspase/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Grupos de Populações Continentais , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Ontologia Genética , Redes Reguladoras de Genes/efeitos dos fármacos , Humanos , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , Anotação de Sequência Molecular , Prognóstico , Proteínas Quinases/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Transcrição/metabolismo , Transcrição Genética/efeitos dos fármacos
4.
Proc Natl Acad Sci U S A ; 118(11)2021 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-33836581

RESUMO

Human clinical trials suggest that inhibition of enzymes in the DNA base excision repair (BER) pathway, such as PARP1 and APE1, can be useful in anticancer strategies when combined with certain DNA-damaging agents or tumor-specific genetic deficiencies. There is also evidence suggesting that inhibition of the BER enzyme 8-oxoguanine DNA glycosylase-1 (OGG1), which initiates repair of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG) and 2,6-diamino-4-hydroxy-5-formamidopyrimidine (Fapy-dG), could be useful in treating certain cancers. Specifically, in acute myeloid leukemia (AML), both the RUNX1-RUNX1T1 fusion and the CBFB-MYH11 subtypes have lower levels of OGG1 expression, which correlate with increased therapeutic-induced cell cytotoxicity and good prognosis for improved, relapse-free survival compared with other AML patients. Here we present data demonstrating that AML cell lines deficient in OGG1 have enhanced sensitivity to cytarabine (cytosine arabinoside [Ara-C]) relative to OGG1-proficient cells. This enhanced cytotoxicity correlated with endogenous oxidatively-induced DNA damage and Ara-C-induced DNA strand breaks, with a large proportion of these breaks occurring at common fragile sites. This lethality was highly specific for Ara-C treatment of AML cells deficient in OGG1, with no other replication stress-inducing agents showing a correlation between cell killing and low OGG1 levels. The mechanism for this preferential toxicity was addressed using in vitro replication assays in which DNA polymerase δ was shown to insert Ara-C opposite 8-oxo-dG, resulting in termination of DNA synthesis. Overall, these data suggest that incorporation of Ara-C opposite unrepaired 8-oxo-dG may be the fundamental mechanism conferring selective toxicity and therapeutic effectiveness in OGG1-deficient AML cells.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Citarabina/farmacologia , DNA Glicosilases/genética , Leucemia Mieloide Aguda/patologia , 8-Hidroxi-2'-Desoxiguanosina/genética , Linhagem Celular Tumoral , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Reparo do DNA , Humanos , Leucemia Mieloide Aguda/enzimologia , RNA Mensageiro/genética
5.
Biochemistry (Mosc) ; 86(3): 307-318, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33838631

RESUMO

In mammals, DNA methylation is an essential epigenetic modification necessary for the maintenance of genome stability, regulation of gene expression, and other processes. Carcinogenesis is accompanied by multiple changes in the DNA methylation pattern and DNA methyltransferase (DNMT) genes; these changes are often associated with poor disease prognosis. Human DNA methyltransferase DNMT3A is responsible for de novo DNA methylation. Missense mutations in the DNMT3A gene occur frequently at the early stages of tumor development and are often observed in hematologic malignances, especially in acute myeloid leukemia (AML), with a prevalence of the R882H mutation. This mutation is the only one that has been extensively studied using both model DNA substrates and cancer cell lines. Biochemical characterization of other DNMT3A mutants is necessary to assess their potential effects on the DNMT3A functioning. In this review, we describe DNMT3A mutations identified in AML with special emphasis on the missense mutations in the DNMT3A catalytic domain. The impact of R882H and less common missense mutations on the DNMT3A activity toward model DNA substrates and in cancer cell lines is discussed together with the underlying molecular mechanisms. Understanding general features of these mechanisms will be useful for further development of novel approaches for early diagnostics of hematologic diseases and personalized cancer therapy.


Assuntos
DNA (Citosina-5-)-Metiltransferases/genética , Leucemia Mieloide Aguda/genética , Mutação , Animais , Humanos , Leucemia Mieloide Aguda/enzimologia
6.
Expert Opin Drug Saf ; 20(7): 791-799, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33853481

RESUMO

INTRODUCTION: FLT3 inhibitors are important drugs in the therapy of FLT3 positive acute myeloid leukemia (AML). Midostaurin was registered in combination with chemotherapy to treat newly diagnosed AML. Gilteritinib and quizartinib demonstrate effectiveness in a randomized trial in relapsed/refractory AML. Several promising FLT3 inhibitors are being evaluated in clinical research. AREAS COVERED: This review will report the safety of FLT3 inhibitors that are registered for acute myeloid leukemia induction and rescue therapy. EXPERT OPINION: In the near future, it is possible that all the FLT3 positive non M3-AML patients will receive a FLT3 inhibitor. Therapy adherence and strategies to mitigate adverse events must be pursued. The treatment with FLT3 inhibitors may be optimized in terms of toxicities with a rational evaluation of antifungal prophylaxis and concomitant therapy, cardiology monitoring, and keeping in mind rare adverse events. Future studies on unfit patients, special populations, and maintenance settings are warranted, together with post-market studies and real-life experiences. Whenever new FLT3 inhibitors will come to the clinic, we could face a scenario in which profound knowledge of effectiveness, toxicities, and off-target effects will be relevant to choose the best drug for each patient.


Assuntos
Leucemia Mieloide Aguda/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Compostos de Anilina/administração & dosagem , Compostos de Anilina/efeitos adversos , Compostos de Anilina/farmacologia , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Benzotiazóis/administração & dosagem , Benzotiazóis/efeitos adversos , Benzotiazóis/farmacologia , Humanos , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/patologia , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/administração & dosagem , Pirazinas/efeitos adversos , Pirazinas/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Estaurosporina/administração & dosagem , Estaurosporina/efeitos adversos , Estaurosporina/análogos & derivados , Estaurosporina/farmacologia
7.
Cell Death Dis ; 12(3): 231, 2021 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-33658491

RESUMO

Acute myeloid leukemia (AML) is a hematological malignancy with high incidence and recurrence rates. Gene expression profiling has revealed that transcriptional overexpression of glioma-associated oncogene 1 (GLI1), a vital gene in the Hedgehog (Hh) signaling pathway, occurs in poor-prognosis AML, and high levels of phosphoinositide-3-kinase, regulatory subunit 1 (PIK3R1) and AKT3 predict shorter overall survival in AML patients. In this study, we discovered that GLI1 overexpression promotes cell proliferation and reduces chemotherapy sensitivity in AML cells while knocking down GLI1 has the opposite effect. Moreover, GLI1 promoted cell cycle progression and led to elevated protein levels of cyclins and cyclin-dependent kinases (CDKs) in AML cells. By luciferase assays and co-immunoprecipitation, we demonstrated that the PI3K/AKT pathway is directly activated by GLI1. GLI1 overexpression significantly accelerates tumor growth and upregulated p-AKT, CDK4, and cyclinD3 in vivo. Notably, the GLI1 inhibitor GANT61 and the CDK4/6 inhibitor PD 0332991 had synergistic effects in promoting Ara-c sensitivity in AML cell lines and patient samples. Collectively, our data demonstrate that GLI1 reduces drug sensitivity by regulating cell cycle through the PI3K/AKT/GSK3/CDK pathway, providing a new perspective for involving GLI1 and CDK4/6 inhibitors in relapsed/refractory (RR) patient treatment.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Quinases Ciclina-Dependentes/metabolismo , Citarabina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Quinase 3 da Glicogênio Sintase/metabolismo , Leucemia Mieloide Aguda/tratamento farmacológico , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína GLI1 em Dedos de Zinco/metabolismo , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proliferação de Células/efeitos dos fármacos , Quinases Ciclina-Dependentes/antagonistas & inibidores , Feminino , Regulação Leucêmica da Expressão Gênica , Células HEK293 , Humanos , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Camundongos Nus , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Pirimidinas/farmacologia , Transdução de Sinais , Células THP-1 , Carga Tumoral/efeitos dos fármacos , Células U937 , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína GLI1 em Dedos de Zinco/antagonistas & inibidores , Proteína GLI1 em Dedos de Zinco/genética
8.
Nat Chem Biol ; 17(5): 567-575, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33664520

RESUMO

The discovery of effective therapeutic treatments for cancer via cell differentiation instead of antiproliferation remains a great challenge. Cyclin-dependent kinase 2 (CDK2) inactivation, which overcomes the differentiation arrest of acute myeloid leukemia (AML) cells, may be a promising method for AML treatment. However, there is no available selective CDK2 inhibitor. More importantly, the inhibition of only the enzymatic function of CDK2 would be insufficient to promote notable AML differentiation. To further validate the role and druggability of CDK2 involved in AML differentiation, a suitable chemical tool is needed. Therefore, we developed first-in-class CDK2-targeted proteolysis-targeting chimeras (PROTACs), which promoted rapid and potent CDK2 degradation in different cell lines without comparable degradation of other targets, and induced remarkable differentiation of AML cell lines and primary patient cells. These data clearly demonstrated the practicality and importance of PROTACs as alternative tools for verifying CDK2 protein functions.


Assuntos
Antineoplásicos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Células Progenitoras Mieloides/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Triazóis/farmacologia , Antineoplásicos/síntese química , Aurora Quinase A/genética , Aurora Quinase A/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Quinase 2 Dependente de Ciclina/genética , Quinase 2 Dependente de Ciclina/metabolismo , Desenho de Fármacos , Descoberta de Drogas , Humanos , Fator de Transcrição Ikaros/genética , Fator de Transcrição Ikaros/metabolismo , Concentração Inibidora 50 , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Células Progenitoras Mieloides/enzimologia , Células Progenitoras Mieloides/patologia , Piperazinas/farmacologia , Cultura Primária de Células , Piridinas/farmacologia , Pirimidinas/farmacologia , Quinazolinas/farmacologia , Transdução de Sinais , Relação Estrutura-Atividade , Transcriptoma , Triazóis/síntese química
9.
Cancer Med ; 10(9): 2946-2955, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33787078

RESUMO

Most acute myeloid leukemia (AML) cells are argininosuccinate synthetase-deficient. Pegylated arginine deiminase (ADI-PEG20) monotherapy depletes circulating arginine, thereby selectively inducing tumor cell death. ADI-PEG20 was shown to induce complete responses in ~10% of relapsed/refractory or poor-risk AML patients. We conducted a phase I, dose-escalation study combining ADI-PEG20 and low-dose cytarabine (LDC) in AML patients. Patients received 20 mg LDC subcutaneously twice daily for 10 days every 28 days and ADI-PEG20 at 18 or 36 mg/m2 (dose levels 1 and 2) intramuscularly weekly. An expansion cohort for the maximal tolerated dose of ADI-PEG20 was planned to further estimate the toxicity and preliminary response of this regimen. The primary endpoints were safety and tolerability. The secondary endpoints were time on treatment, overall survival (OS), overall response rate (ORR), and biomarkers (pharmacodynamics and immunogenicity detection). Twenty-three patients were included in the study, and seventeen patients were in the expansion cohort (dose level 2). No patients developed dose-limiting toxicities. The most common grade III/IV toxicities were thrombocytopenia (61%), anemia (52%), and neutropenia (30%). One had an allergic reaction to ADI-PEG20. The ORR in 18 evaluable patients was 44.4%, with a median OS of 8.0 (4.5-not reached) months. In seven treatment-naïve patients, the ORR was 71.4% and the complete remission rate was 57.1%. The ADI-PEG20 and LDC combination was well-tolerated and resulted in an encouraging ORR. Further combination studies are warranted. (This trial was registered in ClinicalTrials.gov as a Ph1 Study of ADI-PEG20 Plus Low-Dose Cytarabine in Older Patients With AML, NCT02875093).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Citarabina/efeitos adversos , Hidrolases/efeitos adversos , Leucemia Mieloide Aguda/tratamento farmacológico , Polietilenoglicóis/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia/induzido quimicamente , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Arginina/efeitos dos fármacos , Arginina/metabolismo , Argininossuccinato Sintase/deficiência , Citarabina/administração & dosagem , Citarabina/farmacocinética , Esquema de Medicação , Feminino , Humanos , Hidrolases/administração & dosagem , Hidrolases/farmacocinética , Injeções Intramusculares , Injeções Subcutâneas , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/mortalidade , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/farmacocinética , Trombocitopenia/induzido quimicamente , Resultado do Tratamento
10.
Biochem Biophys Res Commun ; 547: 162-168, 2021 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-33610916

RESUMO

Although acute myeloid leukemia (AML) is a highly heterogeneous disease with diverse genetic subsets, one hallmark of AML blasts is myeloid differentiation blockade. Extensive evidence has indicated that differentiation induction therapy represents a promising treatment strategy. Here, we identified that the pharmacological inhibition of the mitochondrial electron transport chain (ETC) complex III by antimycin A inhibits proliferation and promotes cellular differentiation of AML cells. Mechanistically, we showed that the inhibition of dihydroorotate dehydrogenase (DHODH), a rate-limiting enzyme in de novo pyrimidine biosynthesis, is involved in antimycin A-induced differentiation. The activity of antimycin A could be reversed by supplement of excessive amounts of exogenous uridine as well as orotic acid, the product of DHODH. Furthermore, we also found that complex III inhibition exerts a synergistic effect in differentiation induction combined with DHODH inhibitor brequinar as well as with the pyrimidine salvage pathway inhibitor dipyridamole. Collectively, our study uncovered the link between mitochondrial complex III and AML differentiation and may provide further insight into the potential application of mitochondrial complex III inhibitor as a mono or combination treatment in differentiation therapy of AML.


Assuntos
Antimicina A/análogos & derivados , Compostos de Bifenilo/farmacologia , Complexo III da Cadeia de Transporte de Elétrons/antagonistas & inibidores , Leucemia Mieloide Aguda/tratamento farmacológico , Antimicina A/farmacologia , Ciclo Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Complexo III da Cadeia de Transporte de Elétrons/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/patologia , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo
11.
Proc Natl Acad Sci U S A ; 118(8)2021 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-33602808

RESUMO

Cullin-RING (really intersting new gene) E3 ubiquitin ligases (CRLs) are the largest E3 family and direct numerous protein substrates for proteasomal degradation, thereby impacting a myriad of physiological and pathological processes including cancer. To date, there are no reported small-molecule inhibitors of the catalytic activity of CRLs. Here, we describe high-throughput screening and medicinal chemistry optimization efforts that led to the identification of two compounds, 33-11 and KH-4-43, which inhibit E3 CRL4 and exhibit antitumor potential. These compounds bind to CRL4's core catalytic complex, inhibit CRL4-mediated ubiquitination, and cause stabilization of CRL4's substrate CDT1 in cells. Treatment with 33-11 or KH-4-43 in a panel of 36 tumor cell lines revealed cytotoxicity. The antitumor activity was validated by the ability of the compounds to suppress the growth of human tumor xenografts in mice. Mechanistically, the compounds' cytotoxicity was linked to aberrant accumulation of CDT1 that is known to trigger apoptosis. Moreover, a subset of tumor cells was found to express cullin4 proteins at levels as much as 70-fold lower than those in other tumor lines. The low-cullin4-expressing tumor cells appeared to exhibit increased sensitivity to 33-11/KH-4-43, raising a provocative hypothesis for the role of low E3 abundance as a cancer vulnerability.


Assuntos
Antineoplásicos/farmacologia , Biomarcadores Tumorais/metabolismo , Inibidores Enzimáticos/farmacologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Leucemia Mieloide Aguda/tratamento farmacológico , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Animais , Antineoplásicos/química , Apoptose , Biomarcadores Tumorais/genética , Proliferação de Células , Inibidores Enzimáticos/química , Feminino , Humanos , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células Tumorais Cultivadas , Ubiquitina/metabolismo , Ubiquitinação , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Anticancer Res ; 41(2): 731-737, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33517277

RESUMO

BACKGROUND/AIM: FMS-like tyrosine kinase 3 (FLT3) is a class III receptor tyrosine kinase involved in signal transduction underlying survival, proliferation, and differentiation of hematopoietic cells. An internal tandem duplication (ITD) in FLT3 in the juxtamembrane domain is a common mutation causing human acute myeloid leukemia (AML) and activates constitutive signaling. MATERIALS AND METHODS: We evaluated the novel FLT3 inhibitor 5-(4-fluorophenyl)-N-(naphthalen-1-yl)oxazol-2-amine (AIU2008) for the treatment of AML. RESULTS: AIU2008 was designed by modifying FLT3 inhibitor 7c, and showed improved anti-leukemic efficacy in FLT3-ITD-positive AML cells. Specifically, AIU2008 inhibited cell growth and apoptotic death. In addition, AIU2008 down-regulated DNA repair genes involved in homologous recombination and non-homologous end joining. It contributed to the synergistic inhibition of AML cell growth in combination treatment with PARP inhibitors. CONCLUSION: AIU2008 is a promising FLT3 targeting agent, and may be used in combination with PARP inhibitors for the treatment of AML.


Assuntos
Antineoplásicos/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Sequências de Repetição em Tandem , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Dano ao DNA , Reparo do DNA/efeitos dos fármacos , Células HL-60 , Humanos , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/metabolismo
13.
Leuk Res ; 101: 106497, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33385697

RESUMO

Relapsed or refractory (R/R) acute myeloid leukemia (AML) has a poor prognosis, and new therapies are a major clinical need. When mutated, FLT3 drives neoplastic cell proliferation. New drugs (i.e., tyrosine kinase inhibitors, TKIs) showed effectiveness in FLT3-AML and promise to change disease history and outcome. We evaluated the benefit conferred by TKIs in terms of survival, burden of complications and surrogate endpoint of quality of life in a retrospective cohort of 49 FLT3 positive, R/R AML patients. Patients who received TKIs were compared to those treated with conventional chemotherapy. Treatment with TKIs conferred a better OS and wea associated with a lower burden and severity of adverse events. Importantly, patients who received TKIs showed reduced time of hospitalization. In conclusion, treatment with TKI in R/R FLT3-AML was related to a better survival, less and milder AEs, and shorter hospitalization.


Assuntos
Antineoplásicos/administração & dosagem , Leucemia Mieloide Aguda , Mutação , Inibidores de Proteínas Quinases/administração & dosagem , Qualidade de Vida , Tirosina Quinase 3 Semelhante a fms , Adolescente , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/genética , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/metabolismo
15.
Mol Cell Biochem ; 476(5): 1949-1963, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33507464

RESUMO

Focal adhesion kinase (FAK), human myofibrillogenesis regulator-1 (MR-1), ephrin receptor type A4 (EphA4), proto-oncogene tyrosine kinase Src (Src), and protein kinase C (PKC) are important markers in proliferation, survival, and migration in some cancers. However, the significance of each is still unclear in different malignancies, including acute myeloid leukemia (AML). Therefore, this study was conducted to investigate their serum levels in Egyptian adult de novo AML patients (n = 70) against healthy volunteers (n = 20). We managed to study the correlation between each pair and to investigate their association with diagnosis, prognosis, and survival. Serum levels were analyzed using enzyme-linked immunosorbent assay (ELISA). We found that FAK, MR-1, Src, and PKC serum levels were significantly higher in AML patients compared to control (p < 0.0001), and this was associated with significantly lower EphA4 level (p < 0.0001). Interestingly, we also observed a significant negative correlation of FAK (p = 0.027), MR-1 (p = 0.003), Src (p = 0.038), and PKC (p = 0.03) with patients' overall survival (OS) while there was a positive significant correlation between EphA4 and OS (p = 0.007). In conclusion, this study suggests that FAK, MR-1, EphA4, Src, and PKC may be used as early diagnostic and prognostic markers with high sensitivity and specificity in AML patients and thus may be incorporated into the patients' early diagnostic and prognostic panels.


Assuntos
Quinase 1 de Adesão Focal/sangue , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/mortalidade , Proteínas de Neoplasias/sangue , Adulto , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida
16.
Biomolecules ; 10(12)2020 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-33339170

RESUMO

The biological activity of the enzyme glycogen synthase kinase-3 (GSK3) is fulfilled by two paralogs named GSK3α and GSK3ß, which possess both redundancy and specific functions. The upregulated activity of these proteins is linked to the development of disorders such as neurodegenerative disorders (ND) and cancer. Although various chemical inhibitors of these enzymes restore the brain functions in models of ND such as Alzheimer's disease (AD), and reduce the proliferation and survival of cancer cells, the particular contribution of each paralog to these effects remains unclear as these molecules downregulate the activity of both paralogs with a similar efficacy. Moreover, given that GSK3 paralogs phosphorylate more than 100 substrates, the simultaneous inhibition of both enzymes has detrimental effects during long-term inhibition. Although the GSK3ß kinase function has usually been taken as the global GSK3 activity, in the last few years, a growing interest in the study of GSK3α has emerged because several studies have recognized it as the main GSK3 paralog involved in a variety of diseases. This review summarizes the current biological evidence on the role of GSK3α in AD and various types of cancer. We also provide a discussion on some strategies that may lead to the design of the paralog-specific inhibition of GSK3α.


Assuntos
Doença de Alzheimer/metabolismo , Neoplasias Encefálicas/metabolismo , Quinase 3 da Glicogênio Sintase/metabolismo , Doenças Neurodegenerativas/metabolismo , Animais , Neoplasias Encefálicas/enzimologia , Carcinoma Ductal Pancreático/enzimologia , Feminino , Células HL-60 , Humanos , Concentração Inibidora 50 , Leucemia Mieloide Aguda/enzimologia , Neoplasias Pulmonares/enzimologia , Masculino , Simulação de Acoplamento Molecular , Mieloma Múltiplo/enzimologia , Fosforilação , Neoplasias da Próstata/enzimologia , Proteínas Serina-Treonina Quinases , Transdução de Sinais/efeitos dos fármacos
18.
Int J Mol Sci ; 21(22)2020 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-33202543

RESUMO

The bone marrow (BM) microenvironment plays a crucial role in the development and progression of leukemia (AML). Intracellular reactive oxygen species (ROS) are involved in the regulation of the biology of leukemia-initiating cells, where the antioxidant enzyme GPx-3 could be involved as a determinant of cellular self-renewal. Little is known however about the role of the microenvironment in the control of the oxidative metabolism of AML cells. In the present study, a coculture model of BM mesenchymal stromal cells (MSCs) and AML cells (KG1a cell-line and primary BM blasts) was used to explore this metabolic pathway. MSC-contact, rather than culture with MSC-conditioned medium, decreases ROS levels and inhibits the Nrf-2 pathway through overexpression of GPx3 in AML cells. The decrease of ROS levels also inactivates p38MAPK and reduces the proliferation of AML cells. Conversely, contact with AML cells modifies MSCs in that they display an increased oxidative stress and Nrf-2 activation, together with a concomitant lowered expression of GPx-3. Altogether, these experiments suggest that a reciprocal control of oxidative metabolism is initiated by direct cell-cell contact between MSCs and AML cells. GPx-3 expression appears to play a crucial role in this cross-talk and could be involved in the regulation of leukemogenesis.


Assuntos
Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Glutationa Peroxidase/biossíntese , Leucemia Mieloide Aguda/enzimologia , Proteínas de Neoplasias/biossíntese , Microambiente Tumoral , Linhagem Celular Tumoral , Técnicas de Cocultura , Humanos , Leucemia Mieloide Aguda/patologia , Células-Tronco Mesenquimais/enzimologia , Células-Tronco Mesenquimais/patologia , Oxirredução
19.
Leuk Res ; 99: 106462, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33091616

RESUMO

The terminal deoxynucleotidyl transferase (TdT) is a DNA polymerase expressed in acute myeloid leukemias (AMLs), where it may be involved in the generation of NPM1 and FLT3-ITD mutations. We studied the correlations between TdT expression and FLT3-ITD or NPM1 mutations in primary AML samples, and the impact on patients' survival. TdT expression was analyzed in 143 adult AML patients by flow cytometry as percentage of positivity and mean fluorescence intensity (MFI) on blasts. TdT was positive in 49 samples (34.2%), with a median of 48% TdT-positivity (range 7-98) and a median MFI of 2.70 (range 1.23-30.54). FLT3-ITD and NPM1 mutations were present in 24 (16.7%) and 34 (23.7%) cases, respectively. Median TdT expression on blasts was significantly higher in FLT3-ITD+, as compared with FLT3-ITD- AMLs (median 8% vs 0% respectively, p = 0.035). NPM1 mutational status, FLT3-ITD allelic ratio, karyotype, and ELN risk groups, did not correlate with TdT expression or MFI on blasts. TdT + patients had poorer survival as compared to TdT-, but this result was not confirmed by the multivariable analysis, where ELN risk stratification as well as age and type of treatment remained independent prognostic factors for OS. In summary, our results support the possible implication of TdT enzyme in the generation of FLT3-ITD mutations in AML.


Assuntos
DNA Nucleotidilexotransferase/fisiologia , Leucemia Mieloide Aguda/genética , Proteínas de Neoplasias/fisiologia , Tirosina Quinase 3 Semelhante a fms/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , DNA Nucleotidilexotransferase/biossíntese , DNA Nucleotidilexotransferase/genética , Replicação do DNA , DNA de Neoplasias/genética , Feminino , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Mutagênese , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Adulto Jovem
20.
Expert Opin Pharmacother ; 21(18): 2205-2213, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32808831

RESUMO

INTRODUCTION: Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults, but the results for patients with AML are still unsatisfactory. The discovery of new mutations in AML, including IDH mutations, has opened the door for treatment with targeted agents. Ivosidenib is a selective, potent inhibitor of the IDH1 mutant protein. AREAS COVERED: This review summarizes the mechanism of action, safety profile and efficacy of ivosidenib for patients with IDH1-mutated AML. The authors then provide their expert perspectives on the use of the drug including their future perspectives. EXPERT OPINION: Ivosidenib is a promising, most probably practice changing, new drug for the treatment of IDH1-mutated AML. Current phase III trials are ongoing to evaluate the addition of ivosidenib to the current standards-of-care. In the near future, more drug combinations are awaited. Challenges for the future include the development of resistance and establishing the duration of maintenance therapy.


Assuntos
Antineoplásicos/uso terapêutico , Glicina/análogos & derivados , Isocitrato Desidrogenase/antagonistas & inibidores , Leucemia Mieloide Aguda/tratamento farmacológico , Piridinas/uso terapêutico , Adulto , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Ensaios Clínicos como Assunto , Relação Dose-Resposta a Droga , Glicina/administração & dosagem , Glicina/efeitos adversos , Glicina/sangue , Glicina/uso terapêutico , Humanos , Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/enzimologia , Mutação , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Piridinas/sangue , Resultado do Tratamento
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