RESUMO
Acute promyelocytic leukemia (APL) is a type of acute myeloid leukemia (AML) with a high mortality rate, and the production of PML-RARα fusion protein is the cause of its pathogenesis. Our group has synthesized a novel compound, 4-amino-2-trifluoromethyl-phenyl retinate (ATPR), by structural modification of All-trans retinoic acid (ATRA), which has strong cell differentiation-inducing effects and inhibits the expression of PML-RARα. In this study, acute promyelocytic leukemia NB4 cells before and after ATPR induction were analyzed by whole transcriptome microarray, and the expression of lncRNA CONCR was found to be significantly downregulated. The role of CONCR in ATPR-induced cell differentiation and cycle arrest was explored through overexpression and silencing of CONCR. And then the database was used to predict that CONCR may bind to DEAD/H-Box Helicase 11 (DDX11) protein to further explore the role of CONCR binding to DDX11. The results showed that ATPR could reduce the expression of CONCR, and overexpression of CONCR could reverse the ATPR-induced cell differentiation and cycle blocking effect, and conversely silencing of CONCR could promote this effect. RNA immunoprecipitation (RIP) experiments showed that CONCR could bind to DDX11, the protein expression levels of DDX11 and PML-RARα were elevated after overexpression of CONCR. These results suggest that ATPR can regulate the expression of DDX11 through CONCR to affect the expression of PML-RARα fusion protein, which in turn induces the differentiation and maturation of APL cells.
Assuntos
Pontos de Checagem do Ciclo Celular , Diferenciação Celular , RNA Helicases DEAD-box , Leucemia Promielocítica Aguda , Proteínas de Fusão Oncogênica , RNA Longo não Codificante , Transdução de Sinais , Humanos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , RNA Helicases DEAD-box/efeitos dos fármacos , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismo , Regulação Leucêmica da Expressão Gênica , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/patologia , Proteínas de Fusão Oncogênica/efeitos dos fármacos , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , RNA Longo não Codificante/efeitos dos fármacos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Tretinoína/farmacologiaRESUMO
Chromosome translocations involving mixed lineage leukemia (MLL) gene cause acute leukemia with a poor prognosis. MLL is frequently fused with transcription cofactors AF4 (~35%), AF9 (25%) or its paralog ENL (10%). The AHD domain of AF9/ENL binds to AF4, its paralog AFF4, or histone-H3 lysine-79 (H3K79) methyltransferase DOT1L. Formation of AF9/ENL/AF4/AFF4-containing super elongation complexes (SEC) and the catalytic activity of DOT1L are essential for MLL-rearranged leukemia. Protein-protein interactions (PPI) between AF9/ENL and DOT1L/AF4/AFF4 are therefore a potential drug target. Methods: Compound screening followed by medicinal chemistry was used to find inhibitors of such PPIs, which were examined for their biological activities against MLL-rearranged leukemia and other cancer cells. Results: Compound-1 was identified to be a novel small-molecule inhibitor of the AF9/ENL-DOT1L/AF4/AFF4 interaction with IC50s of 0.9-3.5 µM. Pharmacological inhibition of the PPIs significantly reduced SEC and DOT1L-mediated H3K79 methylation in the leukemia cells. Gene profiling shows compound-1 significantly suppressed the gene signatures related to onco-MLL, DOT1L, HoxA9 and Myc. It selectively inhibited proliferation of onco-MLL- or Myc-driven cancer cells and induced cell differentiation and apoptosis. Compound-1 exhibited strong antitumor activity in a mouse model of MLL-rearranged leukemia. Conclusions: The AF9/ENL-DOT1L/AF4/AFF4 interactions are validated to be an anticancer target and compound-1 is a useful in vivo probe for biological studies as well as a pharmacological lead for further drug development.
Assuntos
Antineoplásicos/farmacologia , Leucemia Mieloide Aguda , Proteínas de Fusão Oncogênica , Animais , Expressão Gênica/efeitos dos fármacos , Histona-Lisina N-Metiltransferase/química , Histona-Lisina N-Metiltransferase/efeitos dos fármacos , Histona-Lisina N-Metiltransferase/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Camundongos , Proteínas de Fusão Oncogênica/química , Proteínas de Fusão Oncogênica/efeitos dos fármacos , Proteínas de Fusão Oncogênica/genética , Oncogenes/efeitos dos fármacos , Domínios e Motivos de Interação entre Proteínas , Fatores de Elongação da Transcrição/química , Fatores de Elongação da Transcrição/efeitos dos fármacos , Fatores de Elongação da Transcrição/genéticaAssuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Crizotinibe/farmacologia , Proteínas de Fusão Oncogênica/efeitos dos fármacos , Proteínas de Fusão Oncogênica/genética , Inibidores de Proteínas Quinases/farmacologia , Adulto , Crizotinibe/administração & dosagem , Humanos , Masculino , Inibidores de Proteínas Quinases/administração & dosagem , Resultado do TratamentoRESUMO
The recognition that new cancer drugs can be truly tumour-agnostic based on mechanism-of-action is important for paediatric cancers, where access to novel targeted therapies developed for adult indications has sometimes been problematic. The recently approved drug larotrectinib is an excellent case study of the development of a tumour-agnostic drug relevant to children.
Assuntos
Neoplasias/tratamento farmacológico , Proteínas de Fusão Oncogênica/efeitos dos fármacos , Pediatria , Adulto , Antineoplásicos/uso terapêutico , Criança , Aprovação de Drogas , Humanos , Neoplasias/epidemiologia , Neoplasias/genética , Preparações Farmacêuticas , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêuticoRESUMO
RATIONALE: Acute myeloid leukemia (AML) is a malignantly clonal and highly heterogeneous disease. Although the treatment of AML has brought promising outcomes for younger patients, prognosis of the elderly remains dismal. Innovative regimens are increasingly necessary to be investigated. PATIENT CONCERNS: We present an 86-year-old AML patient with fever, cough, and sputum production. DIAGNOSES: A diagnosis of AML with maturation (AML-M2) and AML1/ETO was made. INTERVENTIONS: The patient was treated with a regimen of Homoharringtonine coupled with arsenic trioxide. OUTCOMES: The AML-M2 patient with AML1/ETO achieved incomplete remission, but showed few toxic side effects and improved survival. Besides, we analyzed the dynamic counts of complete blood cells during the treatment. The count of white blood cell had a positive correlation with the percentage of blast cells (râ=â0.65), both of which had a negative correlation with the percentage of segmented neutrophils (râ=â-0.63, -0.89). LESSONS: Homoharringtonine and arsenic trioxide may induce both the apoptosis and differentiation of leukemic cells in AML-M2 with AML1/ETO.
Assuntos
Antineoplásicos/administração & dosagem , Trióxido de Arsênio/administração & dosagem , Subunidade alfa 2 de Fator de Ligação ao Core/efeitos dos fármacos , Mepesuccinato de Omacetaxina/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Proteínas de Fusão Oncogênica/efeitos dos fármacos , Proteína 1 Parceira de Translocação de RUNX1/efeitos dos fármacos , Idoso de 80 Anos ou mais , Apoptose/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Quimioterapia Combinada , Humanos , MasculinoRESUMO
BACKGROUND: Next-generation sequencing has identified actionable genetic aberrations in intrahepatic cholangiocarcinomas (iCCA), including the fibroblast growth factor receptor 2 (FGFR2) fusions. Derazantinib (ARQ 087), an orally bioavailable, multi-kinase inhibitor with potent pan-FGFR activity, has shown preliminary therapeutic activity against FGFR2 fusion-positive iCCA. METHODS: This multicentre, phase 1/2, open-label study enrolled adult patients with unresectable iCCA with FGFR2 fusion, who progressed, were intolerant or not eligible to first-line chemotherapy (NCT01752920). Subjects received derazantinib in continuous daily doses. Tumour response was assessed according to RECIST 1.1 every 8 weeks. RESULTS: Twenty-nine patients (18 women/11 men; median age, 58.7 years), 2 treatment-naive and 27 who progressed after at least one prior systemic therapy, were enrolled. Overall response rate was 20.7%, disease control rate was 82.8%. Estimated median progression-free survival was 5.7 months (95% CI: 4.04-9.2 months). Treatment-related adverse events (AE) were observed in 27 patients (93.1%, all grades), including asthenia/fatigue (69.0%), eye toxicity (41.4%), and hyperphosphatemia (75.9%). Grade ≥ 3 AEs occurred in 8 patients (27.6%). CONCLUSION: Derazantinib demonstrated encouraging anti-tumour activity and a manageable safety profile in patients with advanced, unresectable iCCA with FGFR2 fusion who progressed after chemotherapy. A pivotal trial of derazantinib in iCCA is ongoing (NCT03230318).
Assuntos
Alcaloides/administração & dosagem , Colangiocarcinoma/tratamento farmacológico , Proteínas de Fusão Oncogênica/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alcaloides/efeitos adversos , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Ensaios Clínicos como Assunto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas de Fusão Oncogênica/efeitos dos fármacos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversosRESUMO
Acute lymphoblastic leukemia (ALL) is an aggressive hematologic malignancy characterized by suboptimal outcomes in the adult age group. Recently, a new subtype called Philadelphia (Ph)-like ALL has been described. This subgroup is characterized by high cytokine receptor and tyrosine kinase signaling expression, resulting in kinase activation through stimulation of two main pathways, the ABL and JAK/STAT pathways. The diagnostic method or approach for Ph-like ALL is still not standardized and efforts are ongoing to identify an easy and applicable diagnostic method. Accurate and standard testing approaches are much needed and this will facilitate better understanding of this subgroup, including better estimation of the prevalence and incidence in different age groups and the clinical outcomes of such new entity. Here, we review the currently available diagnostic tools, activated pathways, and different therapeutic approaches used to target this subgroup.
Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Adolescente , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Criança , Pré-Escolar , Ensaios Clínicos como Assunto , Gerenciamento Clínico , Drogas em Investigação/uso terapêutico , Ativação Enzimática , Feminino , Previsões , Perfilação da Expressão Gênica/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Proteínas de Fusão Oncogênica/efeitos dos fármacos , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/fisiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/classificação , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Prognóstico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Quinases/efeitos dos fármacos , Proteínas Quinases/genética , Proteínas Quinases/fisiologia , Receptores de Citocinas/efeitos dos fármacos , Receptores de Citocinas/genética , Receptores de Citocinas/fisiologia , Distribuição por Sexo , Transdução de Sinais/efeitos dos fármacos , Adulto JovemRESUMO
Many cancer types are driven by oncogenic transcription factors that have been difficult to drug. Transcriptional inhibitors, however, may offer inroads into targeting these cancers. Through chemical genomics screening, we identified that Ewing sarcoma is a disease with preferential sensitivity to THZ1, a covalent small-molecule CDK7/12/13 inhibitor. The selective CDK12/13 inhibitor, THZ531, impairs DNA damage repair in an EWS/FLI-dependent manner, supporting a synthetic lethal relationship between response to THZ1/THZ531 and EWS/FLI expression. The combination of these molecules with PARP inhibitors showed striking synergy in cell viability and DNA damage assays in vitro and in multiple models of Ewing sarcoma, including a PDX, in vivo without hematopoietic toxicity.
Assuntos
Quinases Ciclina-Dependentes/efeitos dos fármacos , Fenilenodiaminas/farmacologia , Proteína Proto-Oncogênica c-fli-1/genética , Pirimidinas/farmacologia , Proteína EWS de Ligação a RNA/genética , Sarcoma de Ewing/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quinases Ciclina-Dependentes/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas de Fusão Oncogênica/efeitos dos fármacos , Proteínas de Fusão Oncogênica/genética , Proteína Proto-Oncogênica c-fli-1/efeitos dos fármacos , Proteína EWS de Ligação a RNA/efeitos dos fármacos , Mutações Sintéticas Letais/efeitos dos fármacos , Mutações Sintéticas Letais/genéticaRESUMO
BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is a rare and highly aggressive disease, that can be described as a member of the family of small round blue cell tumors. The molecular diagnostic marker is the t(11;22)(p13;q12) translocation, which creates an aberrant transcription factor, EWS-WT1, that underlies the oncogenesis of DSRCT. Current treatments are not very effective so new active drugs are needed. Trabectedin, now used as a single agent for the treatment of soft tissue sarcoma, was reported to be active in some pre-treated DSRCT patients. Using JN-DSRCT-1, a cell line derived from DSRCT expressing the EWS-WT1 fusion protein, we investigated the ability of trabectedin to modify the function of the chimeric protein, as in other sarcomas expressing fusion proteins. After detailed characterization of the EWS-WT1 transcripts structure, we investigated the mode of action of trabectedin, looking at the expression and function of the oncogenic chimera. METHODS: We characterized JN-DSRCT-1 cells using cellular approaches (FISH, Clonogenicity assay) and molecular approaches (Sanger sequencing, ChIP, GEP). RESULTS: JN-DSRCT-1 cells were sensitive to trabectedin at nanomolar concentrations. The cell line expresses different variants of EWS-WT1, some already identified in patients. EWS-WT1 mRNA expression was affected by trabectedin and chimeric protein binding on its target gene promoters was reduced. Expression profiling indicated that trabectedin affects the expression of genes involved in cell proliferation and apoptosis. CONCLUSIONS: The JN-DSRCT-1 cell line, in vitro, is sensitive to trabectedin: after drug exposure, EWS-WT1 chimera expression decreases as well as binding on its target promoters. Probably the heterogeneity of chimera transcripts is an obstacle to precisely defining the molecular mode of action of drugs, calling for further cellular models of DSRCT, possibly growing in vivo too, to mimic the biological complexity of this disease.
Assuntos
Tumor Desmoplásico de Pequenas Células Redondas/tratamento farmacológico , Dioxóis/farmacologia , Regulação Neoplásica da Expressão Gênica , Proteínas de Fusão Oncogênica/efeitos dos fármacos , Tetra-Hidroisoquinolinas/farmacologia , Antineoplásicos Alquilantes/farmacologia , Antineoplásicos Alquilantes/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Tumor Desmoplásico de Pequenas Células Redondas/metabolismo , Tumor Desmoplásico de Pequenas Células Redondas/fisiopatologia , Dioxóis/uso terapêutico , Humanos , Proteínas de Fusão Oncogênica/genética , Proteína EWS de Ligação a RNA , Tetra-Hidroisoquinolinas/uso terapêutico , Trabectedina , Proteínas WT1RESUMO
BACKGROUND: CBFA2T3-GLIS2 is a fusion gene found in 17% of non-Down syndrome acute megakaryoblastic leukemia (non-DS AMKL, FAB M7) and in 8% of pediatric cytogenetically normal acute myeloid leukemia (CN-AML, in association with several French-American-British (FAB) subtypes). Children with AML harboring this aberration have a poor outcome, regardless of the FAB subtype. This fusion gene drives a peculiar expression pattern and leads to overexpression of some of Hedgehog-related genes. GLI-similar protein 2 (GLIS2) is closely related to the GLI family, the final effectors of classic Hedgehog pathway. These observations lend compelling support to the application of GLI inhibitors in the treatment of AML with the aberration CBFA2T3-GLIS2. GANT61 is, nowadays, the most potent inhibitor of GLI family proteins. METHODS: We exposed to GANT61 AML cell lines and primary cells positive and negative for CBFA2T3-GLIS2 and analyzed the effect on cellular viability, induction of apoptosis, cell cycle, and expression profile. RESULTS: As compared to AML cells without GLIS2 fusion, GANT61 exposure resulted in higher sensitivity of both cell lines and primary AML cells carrying CBFA2T3-GLIS2 to undergo apoptosis and G1 cell cycle arrest. Remarkably, gene expression studies demonstrated downregulation of GLIS2-specific signature genes in both treated cell lines and primary cells, in comparison with untreated cells. Moreover, chromatin immunoprecipitation analysis revealed direct regulation by GLIS2 chimeric protein of DNMT1 and DNMT3B, two genes implicated in important epigenetic functions. CONCLUSIONS: Our findings indicate that the GLI inhibitor GANT61 may be used to specifically target the CBFA2T3-GLIS2 fusion gene in pediatric AML.
Assuntos
Fatores de Transcrição Kruppel-Like/genética , Leucemia Mieloide Aguda/genética , Proteínas de Fusão Oncogênica/efeitos dos fármacos , Piridinas/farmacologia , Pirimidinas/farmacologia , Proteínas Repressoras/genética , Proteínas Supressoras de Tumor/genética , Proteína GLI1 em Dedos de Zinco/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Criança , Regulação para Baixo/efeitos dos fármacos , Proteínas Hedgehog/genética , Humanos , Fatores de Transcrição Kruppel-Like/fisiologia , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Proteínas de Fusão Oncogênica/genética , Piridinas/uso terapêutico , Pirimidinas/uso terapêutico , Células Tumorais CultivadasRESUMO
BACKGROUND: Fusion proteins have unique oncogenic properties and their identification can be useful either as diagnostic or therapeutic targets. Next generation sequencing data have previously shown a fusion gene formed between Rad51C and ATXN7 genes in the MCF7 breast cancer cell line. However, the existence of this fusion gene in colorectal patient tumor tissues is largely still unknown. METHODS: We evaluated for the presence of Rad51C-ATXN7 fusion gene in colorectal tumors and cells by RT-PCR, PCR, Topo TA cloning, Real time PCR, immunoprecipitation and immunoblotting techniques. RESULTS: We identified two forms of fusion mRNAs between Rad51C and ATXN7 in the colorectal tumors, including a Variant 1 (fusion transcript between Rad51C exons 1-7 and ATXN7 exons 6-13), and a Variant 2 (between Rad51C exons 1-6 and ATXN7 exons 6-13). In silico analysis showed that the Variant 1 produces a truncated protein, whereas the Variant 2 was predicted to produce a fusion protein with molecular weight of 110 KDa. Immunoprecipitation and Western blot analysis further showed a 110 KDa protein in colorectal tumors. 5-Azacytidine treatment of LS-174 T cells caused a 3.51-fold increase in expression of the fusion gene (Variant 2) as compared to no treatment controls evaluated by real time PCR. CONCLUSION: In conclusion we found a fusion gene between DNA repair gene Rad51C and neuro-cerebral ataxia Ataxin-7 gene in colorectal tumors. The in-frame fusion transcript of Variant 2 results in a fusion protein with molecular weight of 110 KDa. In addition, we found that expression of fusion gene is associated with functional impairment of Fanconi Anemia (FA) DNA repair pathway in colorectal tumors. The expression of Rad51C-ATXN7 in tumors warrants further investigation, as it suggests the potential of the fusion gene in treatment and predictive value in colorectal cancers.
Assuntos
Ataxina-7/genética , Clonagem Molecular/métodos , Neoplasias Colorretais/genética , Proteínas de Ligação a DNA/genética , Proteínas de Fusão Oncogênica/genética , Ataxina-7/metabolismo , Azacitidina/farmacologia , Linhagem Celular Tumoral , Neoplasias Colorretais/metabolismo , Simulação por Computador , Metilação de DNA/efeitos dos fármacos , Reparo do DNA , Proteínas de Ligação a DNA/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Variação Genética , Humanos , Peso Molecular , Proteínas de Fusão Oncogênica/efeitos dos fármacos , Proteínas de Fusão Oncogênica/metabolismoRESUMO
Acute promyelocytic leukemia (APL) is a M3 subtype of acute myeloid leukemia (AML). Promyelocytic leukemia (PML)-retinoic acid receptor α (RARα) translocation generally occurs in APL patients and makes APL unique both for diagnosis and treatment. However, some conventional drugs like all-transretinoic acid (ATRA) and arsenic trioxide (ATO), as the preferred ones for APL therapy, induce irreversible resistance and responsible for clinical failure of complete remission. Herein, we screened a library of novel chemical compounds with structural diversity and discovered a novel synthetic small compound, named LG-362B, specifically inhibited the proliferation of APL and induced apoptosis. Notably, the differentiation arrest was also relieved by LG-362B in cultured APL cells and APL mouse models. Moreover, LG-362B overcame the ATRA resistance on cellular differentiation and transplantable APL mice. These positive effects were driven by caspases-mediated degradation of PML-RARα when treated with LG-362B, making it specific to APL and reasonable for ATRA resistance relief. We propose that LG-362B would be a potential candidate agent for the treatment of the relapsed APL with ATRA resistance in the future.
Assuntos
Antineoplásicos/farmacologia , Carbolinas/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Leucemia Promielocítica Aguda/tratamento farmacológico , Proteínas de Fusão Oncogênica/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Leucemia Promielocítica Aguda/patologia , Camundongos , Bibliotecas de Moléculas Pequenas , Tretinoína/farmacologia , Células Tumorais CultivadasAssuntos
Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico/genética , Proteínas de Choque Térmico HSP40/genética , Neoplasias Hepáticas/genética , Proteínas de Fusão Oncogênica/genética , Carcinoma Hepatocelular/tratamento farmacológico , Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico/efeitos dos fármacos , Proteínas de Choque Térmico HSP40/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Proteínas de Fusão Oncogênica/efeitos dos fármacosAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Promielocítica Aguda/tratamento farmacológico , Animais , Antineoplásicos Hormonais/administração & dosagem , Trióxido de Arsênio , Arsenicais/administração & dosagem , Arsenicais/metabolismo , Humanos , Camundongos , Proteínas de Fusão Oncogênica/efeitos dos fármacos , Proteínas de Fusão Oncogênica/metabolismo , Óxidos/administração & dosagem , Óxidos/metabolismo , Tretinoína/administração & dosagem , Tretinoína/metabolismo , Proteína Supressora de Tumor p53/efeitos dos fármacosRESUMO
Obtaining a precise characterization of eosinophilia is crucial, as successful treatment relies on the underlying etiology of the disease. Platelet-derived growth factor receptor alpha-related disorders were first specified in 2008 as a distinct group of clonal eosinophilic disorders with exceptional responsiveness to imatinib. We herein present the case of a man with myeloid neoplasm and eosinophilia in whom a definitive diagnosis could not be adequately made based on histopathological features who was ultimately diagnosed only after extensive molecular analyses and successfully treated with imatinib. In addition, we discuss the diagnostic and therapeutic approaches to treating patients presenting with eosinophilia.
Assuntos
Antineoplásicos/administração & dosagem , Benzamidas/administração & dosagem , Eosinofilia/tratamento farmacológico , Leucemia Mieloide/diagnóstico , Leucemia Mieloide/tratamento farmacológico , Proteínas de Fusão Oncogênica/isolamento & purificação , Piperazinas/administração & dosagem , Pirimidinas/administração & dosagem , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/isolamento & purificação , Fatores de Poliadenilação e Clivagem de mRNA/isolamento & purificação , Adulto , Eosinofilia/metabolismo , Seguimentos , Humanos , Mesilato de Imatinib , Leucemia Mieloide/metabolismo , Masculino , Proteínas de Fusão Oncogênica/efeitos dos fármacos , Proteínas de Fusão Oncogênica/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/efeitos dos fármacos , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Resultado do Tratamento , Fatores de Poliadenilação e Clivagem de mRNA/efeitos dos fármacos , Fatores de Poliadenilação e Clivagem de mRNA/metabolismoRESUMO
Acute promyelocytic leukemia (APL) is characterized by the occurrence of translocations between chromosomes 15 and 17, resulting in generation of a fusion protein of promyelocytic leukemia (PML) and retinoid A receptor (RAR) α. APL cells are unable to differentiate into mature granulocytes since PML-RARα functions as a strong transcriptional repressor for a gene involved in granulocyte differentiation. All-trans retinoic acid (ATRA) is the first agent that has been developed to target specific disease-causing molecules, i.e., ATRA suppresses abnormal functions of oncogenic proteins. Moreover, ATRA facilitates the differentiation of APL cells toward mature granulocytes by changing epigenetic modifiers from corepressor complexes to co-activator complexes on target genes after binding to the ligand-binding domain at the RARα moiety of the PML-RARα oncoprotein. On the other hand, arsenic trioxide (ATO), another promising agent used to treat APL, directly binds to the PML moiety of the PML-RARα protein, causing oxidation and multimerization. ATO enhances the conjugation of small ubiquitin-like modifiers to PML-RARα, followed by ubiquitination and degradation, relieving the genes associated with granulocytic differentiation from suppressive restraint by the oncoprotein. Recent clinical studies have demonstrated that combination therapy with both ATRA and ATO is useful to achieve remission.
Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Arsenicais/uso terapêutico , Leucemia Promielocítica Aguda/tratamento farmacológico , Óxidos/uso terapêutico , Tretinoína/uso terapêutico , Animais , Trióxido de Arsênio , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Sinergismo Farmacológico , Epigênese Genética/efeitos dos fármacos , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Humanos , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/patologia , Proteínas de Fusão Oncogênica/efeitos dos fármacos , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Resultado do TratamentoRESUMO
BACKGROUND: It has recently been reported that the extracts of green tea polyphenol have cancer preventive effects. In this study, we investigated the effect of the natural composition from green tea leaves Catechins on acute promyelocytic leukemia (APL). METHODS: In vitro, APL cell lines NB4, retinoic acid-resistant NB4-R1 and NB4-R2 were treated with different concentrations of Catechins. Cell viability and cell apoptosis were analyzed using MTT assay and flow cytometric assay, respectively. Expression of proteins related to apoptosis and PML-RARα oncoprotein were assessed by Western blot. In vivo anti-tumor activity of Catechins was examined in nude mice xenografted with NB4 cells and in situ cell apoptosis was detected by terminal deoxytransferase-catalyzed DNA nick-end labeling assay. RESULTS: Catechins at micromolar concentration levels significantly inhibited APL cell proliferation and induced cell apoptosis, in association with mitochondria damage, ROS production and caspase activation. The anti-apoptotic Bcl-2 family member Bcl-xL was down regulated, with pro-apoptotic member Bax remaining unchanged. Moreover, Catechins induced the degradation of PML-RARα oncoprotein. Catechins-mediated apoptotic effect was also observed in primary APL cells without affecting normal hematopoietic progenitor cells. In the murine xenograft model, Catechins remarkably inhibited tumor growth and induced in situ leukemic cell apoptosis. CONCLUSIONS: Catechins might be a potential candidate for APL treatment by activating intrinsic apoptotic pathway and targeting PML-RARα oncoprotein.
Assuntos
Apoptose/efeitos dos fármacos , Catequina/farmacologia , Leucemia Promielocítica Aguda/patologia , Proteínas de Fusão Oncogênica/efeitos dos fármacos , Animais , Western Blotting , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Citometria de Fluxo , Humanos , Marcação In Situ das Extremidades Cortadas , Masculino , Camundongos , Camundongos Nus , Proteínas de Fusão Oncogênica/metabolismo , Chá , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
If looking for a mnemonic to remember the relevant facts about acute promyelocytic leukemia (APL), one just has to remember that APL is a disease of A's. It is acute and it is highly sensitive to treatment with anthracyclines, all-trans-retinoic acid (RA) and arsenic trioxide (ATO). The presence of fusions involving the retinoic acid receptor alpha (RARA) is without question the central player driving APL and dictating the response of this disease to these therapeutic agents. However, beyond this knowledge, the molecular mechanisms that contribute to the complicated pathogenesis and the response to treatment of APL are not completely defined. As more is understood about this hematological malignancy, there are more opportunities to refine and improve treatment based on this knowledge. In this review article, we discuss the response of APL to these "A" therapies.
Assuntos
Antraciclinas/uso terapêutico , Antibióticos Antineoplásicos/uso terapêutico , Arsenicais/uso terapêutico , Células Precursoras de Granulócitos/efeitos dos fármacos , Leucemia Promielocítica Aguda/tratamento farmacológico , Óxidos/uso terapêutico , Tretinoína/uso terapêutico , Antraciclinas/farmacologia , Antibióticos Antineoplásicos/farmacologia , Trióxido de Arsênio , Arsenicais/farmacologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Regulação Leucêmica da Expressão Gênica , Humanos , Terapia de Alvo Molecular , Proteínas de Neoplasias/efeitos dos fármacos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/fisiologia , Proteínas de Fusão Oncogênica/efeitos dos fármacos , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/fisiologia , Óxidos/farmacologia , Inibidores da Topoisomerase II/farmacologia , Inibidores da Topoisomerase II/uso terapêutico , Transcrição Gênica/genética , Tretinoína/farmacologiaRESUMO
Crizotinib is an ATP-competitive small-molecule inhibitor of the receptor tyrosine kinases (RTK) c-Met, anaplastic lymphoma kinase (ALK), and ROS1. There is convincing clinical evidence for the effectiveness in non-small-cell lung cancer (NSCLC) harboring EML4-ALK rearrangements resulting in constitutional activation of the ALK-RTK. The drug is approved for this entity, which represents no more than 3-5% of all NSCLC. However, in this population, impressive response rates are generated. The same seems to be true for ROS-1 rearrangements; however, these only occur in approximately 1% of all NSCLC. The role in c-Met altered cancers needs to be determined. Toxicities include visual impairment, nausea, peripheral edema, QT-prolongation, and liver enzyme elevation. Also, the occurrence of renal cysts is reported. Fluorescence in situ hybridization (FISH) detecting the ALK rearrangement has to be performed on tumor tissue to predict crizotinib efficacy. The role of immunohistochemistry in this setting needs to be determined. It has high concordance with FISH results when strongly positive or completely negative. The high efficacy of crizotinib in ALK- and ROS-positive lung cancer as new molecular targets beside the epidermal growth factor receptor (EGFR) underscores the importance of molecular typing in NSCLC.