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2.
Adv Exp Med Biol ; 1207: 601-613, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32671778

RESUMO

Leukemia is a malignant clonal disease that originates from hematopoietic stem cells. As in-depth research examines the molecular biology and immunology of the hematopoietic system, leukemia treatment has evolved from a single cytotoxic drug to treatments that inducing differentiation and apoptosis. Meanwhile, autophagy has become a growing concern as a new form of cell death. The immune response, hematopoietic stem cell differentiation, and drug resistance of tumor cells are all potentially affected by autophagy. Regulating autophagy may become one of the promising directions in the field of targeted therapy.


Assuntos
Autofagia , Leucemia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Autofagia/efeitos dos fármacos , Células-Tronco Hematopoéticas/patologia , Humanos , Leucemia/tratamento farmacológico , Leucemia/patologia
4.
Anticancer Res ; 40(6): 3055-3063, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487599

RESUMO

The idea of utilizing poly-ADP-ribose polymerase inhibitors (PARPi) as therapeutics for cancer has grown in popularity since its original approval for clinical usage in treatment of BRCA DNA repair-associated-mutated ovarian cancer. In this study, we evaluated experimental data regarding in vitro studies utilizing PARPi as a treatment for tyrosine kinase (TK)-dependent leukemia. Studies from 2015 to 2019 were compiled and the ones with most relevant TK pathways and PARP inhibition were analyzed. PARPi showed activity against many leukemia cell lines and samples from patients with primary leukemia, especially when combined with other signaling pathway inhibitor drugs, improving upon the hypothesis that the utilization of PARPi has potential as a new therapeutic approach in treatment of primary leukemia and TK-dependent leukemia.


Assuntos
Leucemia/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Humanos , Leucemia/patologia
5.
Cancer Treat Rev ; 88: 102026, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32592909

RESUMO

Progress in cancer therapy changed the outcome of many patients and moved therapy from chemotherapy agents to targeted drugs. Targeted drugs already changed the clinical practice in treatment of leukemias, such as imatinib (BCR/ABL inhibitor) in chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL), ibrutinib (Bruton's tyrosine kinase inhibitor) in chronic lymphocytic leukemia (CLL), venetoclax (BCL2 inhibitor) in CLL and acute myeloid leukemia (AML) or midostaurin (FLT3 inhibitor) in AML. In this review, we focused on DNA damage response (DDR) inhibition, specifically on inhibition of ATR-CHK1 pathway. Cancer cells harbor often defects in different DDR pathways, which render them vulnerable to DDR inhibition. Some DDR inhibitors showed interesting single-agent activity even in the absence of cytotoxic drug especially in cancers with underlying defects in DDR or DNA replication. Almost no mutations were found in ATR and CHEK1 genes in leukemia patients. Together with the fact that ATR-CHK1 pathway is essential for cell development and survival of leukemia cells, it represents a promising therapeutic target for treatment of leukemia. ATR-CHK1 inhibition showed excellent results in preclinical testing in acute and chronic leukemias. However, results in clinical trials are so far insufficient. Therefore, the ongoing and future clinical trials will decide on the success of ATR/CHK1 inhibitors in clinical practice of leukemia treatment.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Quinase 1 do Ponto de Checagem/metabolismo , Leucemia/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Doença Aguda , Animais , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Quinase 1 do Ponto de Checagem/antagonistas & inibidores , Doença Crônica , Dano ao DNA , Humanos , Leucemia/genética , Leucemia/metabolismo , Leucemia/patologia , Terapia de Alvo Molecular , Ensaios Clínicos Controlados Aleatórios como Assunto
6.
Leuk Res ; 94: 106383, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32460059

RESUMO

Metformin is an anti-diabetic drug known to have anticancer activity by inhibiting mechanistic target of rapamycin (mTOR); however, other molecular mechanisms may also be involved. In this study, we examined the effects of metformin on the activity of receptor tyrosine kinases of the TAM (TYRO3, AXL, and MERTK) family, which have important roles in leukemia cell growth. The results indicated that metformin suppressed the in vitro growth of four leukemia cell lines, OCI/AML2, OCI/AML3, THP-1, and K562, in a dose-dependent manner, which corresponded to the downregulation of the expression and phosphorylation of AXL and inhibition of its downstream targets such as phosphorylation of STAT3. Furthermore, metformin augmented the suppressive effects of a small-molecule AXL inhibitor TP-0903 on the growth of OCI/AML3 and K562 cells and prevented doxorubicin-induced AXL activation in K562 cells, which induces chemoresistance in leukemia cells, thus potentiating doxorubicin anti-proliferative effects. Given that metformin also downregulated expression of TYRO3 and phosphorylation of MERTK, these findings indicate that anti-leukemic effects exerted by metformin could be partly due to the inhibition of TAM kinases. Thus, metformin has a clinical potential for patients with leukemia cells positive for AXL and the other TAM proteins as well as activated mTOR.


Assuntos
Regulação para Baixo/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Leucemia , Metformina/farmacologia , Proteínas Proto-Oncogênicas/biossíntese , Receptores Proteína Tirosina Quinases/biossíntese , Humanos , Células K562 , Leucemia/tratamento farmacológico , Leucemia/enzimologia , Leucemia/patologia , Células THP-1
8.
Phytomedicine ; 70: 153215, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32388040

RESUMO

BACKGROUND: Recalcitrant cancers appear as a major obstacle to chemotherapy, prompting scientists to intensify the search for novel drugs to tackle the cell lines expressing multi-drug resistant (MDR) phenotypes. PURPOSE: The purpose of this study was to evaluate the antiproliferative potential of a ferrulic acid derivative, 8,8-bis-(dihydroconiferyl)-diferulate (DHCF2) on a panel of 18 cancer cell lines, including various sensitive and drug-resistant phenotypes, belonging to human and animals. The mode of induction of cell death by this compound was further studied. METHODS: The antiproliferative activity, autophagy, ferroptotic and necroptotic cell death were evaluated by the resazurin reduction assay (RRA). CCRF-CEM leukemia cells were used for all mechanistic studies. A caspase-Glo assay was applied to evaluate the activity of caspases. Cell cycle analysis (PI staining), apoptosis (annexin V/PI staining), mitochondrial membrane potential (MMP) (JC-1) and reactive oxygen species (ROS) (H2DCFH-DA) were assessed by flow cytometry. RESULTS: DHCF2 demonstrated impressive cytotoxic effects towards the 18 cancer cell lines tested, with IC50 values all below 6.5 µM. The obtained IC50 values were in the range of 1.17 µM (towards CCRF-CEM leukemia cells) to 6.34 µM (towards drug-resistant HCT116 p53-/- human colon adenocarcinoma cells) for DHCF2 and from 0.02 µM (against CCRF-CEM cells) to 122.96 µM (against multidrug-resistant CEM/ADR5000 leukemia cells) for the reference drug, doxorubicin. DHCF2 had IC50 values lower than those of doxorubicin, against CEM/ADR5000 cells and on some melanoma cell lines, such as MaMel-80a cells, Mel-2a cells, MV3 cells and SKMel-505 cells. DHCF2 induced autophagy as well as apoptosis in CCRF-CEM cells though caspases activation, MMP alteration and increase of ROS production. CONCLUSION: The studied diferulic acid, DHCF2, is a promising antiproliferative compound. It deserves further indepth investigations with the ultimate aim to develop a novel drug to fight cancer drug resistance.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/toxicidade , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral/efeitos dos fármacos , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Leucemia/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/uso terapêutico , Doxorrubicina/uso terapêutico , Doxorrubicina/toxicidade , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Humanos , Camundongos , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Extratos Vegetais/toxicidade
9.
Nat Commun ; 11(1): 2369, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32398749

RESUMO

Despite growing awareness of the biologic features underlying MLL-rearranged leukemia, targeted therapies for this leukemia have remained elusive and clinical outcomes remain dismal. MBNL1, a protein involved in alternative splicing, is consistently overexpressed in MLL-rearranged leukemias. We found that MBNL1 loss significantly impairs propagation of murine and human MLL-rearranged leukemia in vitro and in vivo. Through transcriptomic profiling of our experimental systems, we show that in leukemic cells, MBNL1 regulates alternative splicing (predominantly intron exclusion) of several genes including those essential for MLL-rearranged leukemogenesis, such as DOT1L and SETD1A. We finally show that selective leukemic cell death is achievable with a small molecule inhibitor of MBNL1. These findings provide the basis for a new therapeutic target in MLL-rearranged leukemia and act as further validation of a burgeoning paradigm in targeted therapy, namely the disruption of cancer-specific splicing programs through the targeting of selectively essential RNA binding proteins.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Regulação Neoplásica da Expressão Gênica , Leucemia/genética , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas de Fusão Oncogênica/genética , Proteínas de Ligação a RNA/metabolismo , Processamento Alternativo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Transplante de Medula Óssea , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Conjuntos de Dados como Assunto , Técnicas de Silenciamento de Genes , Rearranjo Gênico , Histona-Lisina N-Metiltransferase/genética , Humanos , Íntrons/genética , Leucemia/tratamento farmacológico , Leucemia/patologia , Camundongos , Camundongos Knockout , Cultura Primária de Células , RNA Interferente Pequeno/metabolismo , Proteínas de Ligação a RNA/antagonistas & inibidores , Proteínas de Ligação a RNA/genética , RNA-Seq , Quimeras de Transplante , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Transl Res ; 220: 167-181, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32275896

RESUMO

Despite advances in antimicrobial treatments, infection remains a common complication of intensive chemotherapy in patients with acute leukemia. It has become progressively apparent that the current antimicrobial focus has shortcomings that result from disruption of the commensal microbial communities of the gut. These effects, collectively known as dysbiosis, have been increasingly associated worldwide with growing complications such as Clostridioides difficile infection, systemic infections, and antibiotic resistance. A revision of the current practice is overdue. Several innovative concepts have been proposed and tested in animal models and humans, with the overarching goal of preventing damage to the microbiota and facilitating its recovery. In this review, we discuss these approaches, examine critical knowledge gaps, and explore how they may be filled in future research.


Assuntos
Antineoplásicos/efeitos adversos , Infecções Bacterianas/prevenção & controle , Microbioma Gastrointestinal/efeitos dos fármacos , Leucemia/tratamento farmacológico , Doença Aguda , Animais , Antibacterianos/uso terapêutico , Disbiose/induzido quimicamente , Microbioma Gastrointestinal/fisiologia , Transplante de Células-Tronco Hematopoéticas , Humanos , Leucemia/complicações , Leucemia/microbiologia
11.
Nat Commun ; 11(1): 1879, 2020 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-32312992

RESUMO

Bryostatin 1 is a marine natural product under investigation for HIV/AIDS eradication, the treatment of neurological disorders, and enhanced CAR T/NK cell immunotherapy. Despite its promising activity, bryostatin 1 is neither evolved nor optimized for the treatment of human disease. Here we report the design, synthesis, and biological evaluation of several close-in analogs of bryostatin 1. Using a function-oriented synthesis approach, we synthesize a series of bryostatin analogs designed to maintain affinity for bryostatin's target protein kinase C (PKC) while enabling exploration of their divergent biological functions. Our late-stage diversification strategy provides efficient access to a library of bryostatin analogs, which per our design retain affinity for PKC but exhibit variable PKC translocation kinetics. We further demonstrate that select analogs potently increase cell surface expression of CD22, a promising CAR T cell target for the treatment of leukemias, highlighting the clinical potential of bryostatin analogs for enhancing targeted immunotherapies.


Assuntos
Briostatinas/biossíntese , Briostatinas/farmacologia , Imunoterapia/métodos , Neoplasias/tratamento farmacológico , Proteína Quinase C/metabolismo , Briostatinas/química , Linhagem Celular Tumoral , Humanos , Leucemia/tratamento farmacológico , Modelos Moleculares , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Linfócitos T
12.
Int J Oncol ; 56(3): 772-782, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32124958

RESUMO

Cofilin is associated with cell differentiation; however, to the best of our knowledge, no data have indicated an association between the cofilin 1 pathway and leukemia cell differentiation. The present study investigated the involvement of the cofilin 1 signaling pathway in diallyl disulfide (DADS)­induced differentiation and the inhibitory effects on the proliferation, migration, and invasion of human leukemia HL­60 cells. First, it was identified that 8 µM DADS suppressed cell proliferation, migration and invasion, and induced differentiation based on the reduced nitroblue tetrazolium ability and increased CD11b and CD33 expression. DADS significantly downregulated the expression of cofilin 1 and phosphorylated cofilin 1 in HL­60 leukemia cells. Second, it was verified that silencing cofilin 1 markedly promoted 8 µM DADS­induced differentiation and the inhibitory effect on cell proliferation and invasion. Overexpression of cofilin 1 obviously suppressed 8 µM DADS­induced differentiation and the inhibitory effect on cell proliferation and invasion. Third, the present study examined the mechanisms by which 8 µM DADS decreases cofilin 1 expression and activation. The results revealed that 8 µM DADS inhibited the mRNA and protein expression of Rac1, Rho­associated protein kinase 1 (ROCK1) and LIM domain kinase 1 (LIMK1) as well as the phosphorylation of LIMK1 in HL­60 cells, while 8 µM DADS enhanced the effects of the Rac1­ROCK1­LIMK1 pathway in cells overexpressing cofilin 1 compared with that in control HL­60 cells. These results suggest that the anticancer function of DADS on HL­60 leukemia cells is regulated by the Rac1­ROCK1­LIMK1­cofilin 1 pathway, indicating that DADS could be a promising anti­leukemia therapeutic compound.


Assuntos
Compostos Alílicos/farmacologia , Antineoplásicos/farmacologia , Cofilina 1/genética , Cofilina 1/metabolismo , Dissulfetos/farmacologia , Leucemia/metabolismo , Diferenciação Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HL-60 , Humanos , Leucemia/tratamento farmacológico , Leucemia/genética , Quinases Lim/metabolismo , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proteínas rac1 de Ligação ao GTP/metabolismo , Quinases Associadas a rho/metabolismo
13.
Med Sci Monit ; 26: e921288, 2020 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-32146479

RESUMO

BACKGROUND Leukemia is common in aging adults and has very high mortality worldwide. The present study was designed to investigate the therapeutic efficacy of miR-18a inhibitor against WEHI-3 and THP-1 leukemia cells. MATERIAL AND METHODS The changes in miR-18a inhibitor-transfected WEHI-3 and THP-1 cell proliferative potential was measured by use of the Cell Counting Kit-8 assay. Apoptotic changes were analyzed by electron microscopy, and evaluation of PI3K, AKT, mTOR, and PTEN expression was assessed by RT-qPCR assay. RESULTS Transfection of miR-18a inhibitor significantly (P<0.05) suppressed the proliferative potential of WEHI-3 and THP-1 cells. The WEHI-3 cells showed the presence of characteristic apoptotic bodies on transfection with miR-18a inhibitor at 48 h. Flow cytometry showed that miR-18a inhibitor transfection significantly (P<0.05) increased the WEHI-3 cell percentage in G1 phase. The transfection of miR-18a inhibitor significantly (P<0.05) promoted apoptosis in WEHI-3 cells. In WEHI-3 cells, miR-18a inhibitor transfection markedly suppressed the expression of PI3K, AKT, and mTOR mRNA. The expression of PTEN mRNA was significantly (P<0.05) upregulated by miR-18a inhibitor transfection in WEHI-3 cells. CONCLUSIONS The present study investigated the therapeutic efficacy of miR-18a inhibitor against WEHI-3 and THP1 leukemia cells. The study demonstrated that miR-18a inhibitor suppressed the proliferative potential of WEHI-3 and THP1 cells and activated apoptotic process through upregulation of PTEN mRNA expression. Therefore, miR-18a inhibitor can be of therapeutic importance for the treatment of leukemia.


Assuntos
Proliferação de Células/efeitos dos fármacos , Leucemia/patologia , MicroRNAs/antagonistas & inibidores , PTEN Fosfo-Hidrolase/metabolismo , Apoptose , Regulação Leucêmica da Expressão Gênica , Humanos , Leucemia/tratamento farmacológico , Células THP-1 , Transfecção , Regulação para Cima
14.
Adv Exp Med Biol ; 1219: 259-293, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32130704

RESUMO

The human body requires a constant delivery of fresh blood cells that are needed to maintain body homeostasis. Hematopoiesis is the process that drives the formation of new blood cells from a single stem cell. This is a complex, orchestrated and tightly regulated process that occurs within the bone marrow. When such process is faulty or deregulated, leukemia arises, develops and thrives by subverting normal hematopoiesis and availing the supplies of this rich milieu.In this book chapter we will describe and characterize the bone marrow microenvironment and its key importance for leukemia expansion. The several components of the bone marrow niche, their interaction with the leukemic cells and the cellular pathways activated within the malignant cells will be emphasized. Finally, novel therapeutic strategies to target this sibling interaction will also be discussed.


Assuntos
Medula Óssea/metabolismo , Progressão da Doença , Leucemia/patologia , Microambiente Tumoral , Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Hematopoese/efeitos dos fármacos , Humanos , Leucemia/tratamento farmacológico , Nicho de Células-Tronco/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos
15.
Phys Ther ; 100(3): 509-522, 2020 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-32044966

RESUMO

BACKGROUND: Glucocorticoids used to treat childhood leukemia and lymphoma can result in osteonecrosis, leading to physical dysfunction and pain. Improving survival rates warrants research into long-term outcomes among this population. OBJECTIVE: The objective of this study was to compare the physical function and quality of life (QOL) of survivors of childhood cancer who had an osteonecrosis history with that of survivors who had no osteonecrosis history and with that of people who were healthy (controls). DESIGN: This was a cross-sectional study. METHODS: This study included St Jude Lifetime Cohort Study participants who were ≥ 10 years from the diagnosis of childhood leukemia or lymphoma and ≥ 18 years old; 135 had osteonecrosis (52.5% men; mean age = 27.7 [SD = 6.08] years) and 1560 had no osteonecrosis history (52.4% men; mean age = 33.3 [SD = 8.54] years). This study also included 272 people who were from the community and who were healthy (community controls) (47.7% men; mean age = 35.1 [SD = 10.46] years). The participants completed functional assessments and questionnaires about QOL. RESULTS: Survivors with osteonecrosis scored lower than other survivors and controls for dorsiflexion strength (mean score = 16.50 [SD = 7.91] vs 24.17 [SD = 8.61] N·m/kg) and scored lower than controls for flexibility with the sit-and-reach test (20.61 [SD = 9.70] vs 23.96 [SD = 10.73] cm), function on the Physical Performance Test (mean score = 22.73 [SD = 2.05] vs 23.58 [SD = 0.88]), and mobility on the Timed "Up & Go" Test (5.66 [SD = 2.25] vs 5.12 [SD = 1.28] seconds). Survivors with hip osteonecrosis requiring surgery scored lower than survivors without osteonecrosis for dorsiflexion strength (13.75 [SD = 8.82] vs 18.48 [SD = 9.04] N·m/kg), flexibility (15.79 [SD = 8.93] vs 20.37 [SD = 10.14] cm), and endurance on the 6-minute walk test (523.50 [SD = 103.00] vs 572.10 [SD = 102.40] m). LIMITATIONS: Because some eligible survivors declined to participate, possible selection bias was a limitation of this study. CONCLUSIONS: Survivors of childhood leukemia and lymphoma with and without osteonecrosis demonstrated impaired physical performance and reported reduced QOL compared with controls, with those requiring surgery for osteonecrosis most at risk for impairments. It may be beneficial to provide strengthening, flexibility, and endurance interventions for patients who have pediatric cancer and osteonecrosis for long-term function.


Assuntos
Sobreviventes de Câncer , Leucemia/tratamento farmacológico , Linfoma/tratamento farmacológico , Osteonecrose/fisiopatologia , Desempenho Físico Funcional , Qualidade de Vida , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Estudos Transversais , Feminino , Glucocorticoides/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Força Muscular , Osteonecrose/induzido quimicamente , Osteonecrose/cirurgia , Amplitude de Movimento Articular , Participação Social , Teste de Caminhada
16.
Yakugaku Zasshi ; 140(2): 229-271, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32009046

RESUMO

Outcomes of treatment for malignant pediatric tumors including leukemia are improving by conventional multimodal treatment with strong chemotherapy, surgical resection, radiotherapy, and bone marrow transplantation. However, patients with advanced neuroblastoma, metastatic Ewing's sarcoma family of tumor (ESFT), and metastatic osteosarcoma continue to have an extremely poor prognosis. Therefore novel therapeutic strategies are urgently needed to improve their survival. Apoptotic cell death is a key mechanism for normal cellular homeostasis. Intact apoptotic mechanisms are pivotal for embryonic development, tissue remodeling, immune regulation, and tumor regression. Genetic aberrations disrupting programmed cell death often underpin tumorigenesis and drug resistance. Moreover, it has been suggested that apoptosis or cell differentiation proceeds to spontaneous regression in early stage neuroblastoma. Therefore apoptosis or cell differentiation is a critical event in this cancer. We extracted many compounds from natural plants (Angelica keiskei, Alpinia officiarum, Lycaria puchury-major, Brassica rapa) or synthesized cyclophane pyridine, indirubin derivatives, vitamin K3 derivatives, burchellin derivatives, and GANT61, and examined their effects on apoptosis, cell differentiation, and cell cycle in neuroblastoma and ESFT cell lines compared with normal cells. Some compounds were very effective against these tumor cells. These results suggest that they may be applicable as an efficacious and safe drug for the treatment of malignant pediatric tumors.


Assuntos
Desenvolvimento de Medicamentos , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Apoptose , Diferenciação Celular , Criança , Pré-Escolar , Genes Supressores de Tumor , Humanos , Lactente , Leucemia/tratamento farmacológico , Leucemia/patologia , Neoplasias/patologia , Extratos Vegetais , Prognóstico
17.
Molecules ; 25(1)2020 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-31947824

RESUMO

Herein, we design and synthesize an array of benzofuro[3,2-c]quinolines starting from 3-(2-methoxyphenyl)quinolin-4(1H)ones via a sequential chlorination/demethylation, intramolecular cyclization pathway. This sequential transformation was efficient, conducted under metal-free and mild reaction conditions, and yielded corresponding benzofuro[3,2-c]quinolines in high yields. In vitro biological evaluation indicated that such type of compounds showed excellent antileukemia activity and selectivity, and therefore may offer a promising hit compound for developing antileukemia compounds.


Assuntos
Antineoplásicos , Desenho de Fármacos , Leucemia , Quinolinas , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Leucemia/tratamento farmacológico , Leucemia/metabolismo , Leucemia/patologia , Quinolinas/síntese química , Quinolinas/química , Quinolinas/farmacologia
18.
Mol Med Rep ; 21(3): 1035-1042, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31922221

RESUMO

Hematologic malignancy is a serious disease that develops quickly and aggressively, severely threatening human health owing to its high mortality. The current study aimed to evaluate the antitumor effects of isoferulic acid (IFA) on leukemia cells and investigate the possible molecular mechanisms. Hematologic cancer cell lines (Raji, K562 and Jurkat) were treated with IFA in a dose­dependent manner and proliferation was measured by a cell proliferation assay. Cell cycle arrest was detected via flow cytometry using propidium iodide (PI) staining. Cell apoptosis and apoptosis­associated signal pathways were analyzed via Annexin V/PI staining and western blot assays, respectively. IFA inhibited cell viability, induced cell apoptosis and triggered cell cycle arrest in G2/M phase in Raji, K562, and Jurkat cells in a dose­dependent manner. In response to IFA treatment, the levels of cleaved poly(ADP­ribose) polymerase and cleaved caspase­3 were increased in Jurkat and K562 cells, which was associated with increased phosphorylation of Cdc2 and reduction of Cyclin B1 levels. IFA remarkably attenuated the phosphorylation of mTOR and Akt in Jurkat cells. Collectively, the present data suggested that IFA had therapeutic effects on Jurkat, K562, and Raji cells, indicating it as a promising candidate for the treatment of hematologic malignancy.


Assuntos
Cinamatos/farmacologia , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Leucemia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Humanos , Células Jurkat , Células K562 , Leucemia/tratamento farmacológico , Leucemia/metabolismo , Leucemia/patologia , Pontos de Checagem da Fase M do Ciclo Celular
20.
Mol Immunol ; 118: 201-209, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31896496

RESUMO

Trigonelline, one of the alkaloids contained in coffee, is important not only as one of the constituents of aroma and flavor in coffee but also as a useful source of nutrition. Its anti-microbial, anti-carcinogenic, and anti-hyperglycemic effects have been investigated in previous studies. However, there have not been any studies examining the anti-degranulation effect of trigonelline. In this study, the anti-degranulation effect of trigonelline was evaluated in in vitro and in vivo models using a rat basophilic leukemia cell line, RBL-2H3 cells, and a passive cutaneous anaphylaxis (PCA) reaction in mice, respectively. In the ß-hexosaminidase release assay, trigonelline effectively suppressed antigen-induced degranulation of RBL-2H3 cells in a dose-dependent manner without cytotoxicity. Trigonelline also inhibited FcεRI-mediated intracellular signaling pathways, such as phosphorylation of PLCγ1, PI3 K, and Akt, in antigen-stimulated RBL-2H3 cells and suppressed the PCA response in mice. Moreover, trigonelline also inhibited the microtubule formation in RBL-2H3 cells, indicating that trigonelline could inhibit IgE-sensitized mast cell degranulation by attenuating both the intracellular calcium-dependent and independent pathways. These results revealed that trigonelline possesses the anti-degranulation effect against the development of allergic diseases.


Assuntos
Alcaloides/farmacologia , Degranulação Celular/efeitos dos fármacos , Animais , Antialérgicos/farmacologia , Cálcio/metabolismo , Linhagem Celular Tumoral , Feminino , Hipersensibilidade/tratamento farmacológico , Hipersensibilidade/metabolismo , Imunoglobulina E/metabolismo , Leucemia/tratamento farmacológico , Leucemia/metabolismo , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Anafilaxia Cutânea Passiva/efeitos dos fármacos , Extratos Vegetais/farmacologia , Ratos , Transdução de Sinais/efeitos dos fármacos
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