RESUMO
Osimertinib is a third-generation covalent EGFR inhibitor that is used in treating non-small cell lung cancer. First-generation EGFR inhibitors were found to elicit pro-differentiation effect on acute myeloid leukemia (AML) cells in preclinical studies, but clinical trials yielded mostly negative results. Here, we report that osimertinib selectively induced apoptosis of CD34+ leukemia stem/progenitor cells but not CD34- cells in EGFR-negative AML and chronic myeloid leukemia (CML). Covalent binding of osimertinib to CD34 at cysteines 199 and 177 and suppression of Src family kinases (SFK) and downstream STAT3 activation contributed to osimertinib-induced cell death. SFK and STAT3 inhibition induced synthetic lethality with osimertinib in primary CD34+ cells. CD34 expression was elevated in AML cells compared with their normal counterparts. Genomic, transcriptomic, and proteomic profiling identified mutation and gene expression signatures of patients with AML with high CD34 expression, and univariate and multivariate analyses indicated the adverse prognostic significance of high expression of CD34. Osimertinib treatment induced responses in AML patient-derived xenograft models that correlated with CD34 expression while sparing normal CD34+ cells. Clinical responses were observed in two patients with CD34high AML who were treated with osimertinib on a compassionate-use basis. These findings reveal the therapeutic potential of osimertinib for treating CD34high AML and CML and describe an EGFR-independent mechanism of osimertinib-induced cell death in myeloid leukemia. SIGNIFICANCE: Osimertinib binds CD34 and selectively kills CD34+ leukemia cells to induce remission in preclinical models and patients with AML with a high percentage of CD34+ blasts, providing therapeutic options for myeloid leukemia patients.
Assuntos
Acrilamidas , Compostos de Anilina , Carcinoma Pulmonar de Células não Pequenas , Indóis , Leucemia Mieloide Aguda , Neoplasias Pulmonares , Pirimidinas , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proteômica , Proliferação de Células , Neoplasias Pulmonares/metabolismo , Leucemia Mieloide Aguda/genética , Células Progenitoras Mieloides , Receptores ErbB/metabolismo , Antígenos CD34/metabolismo , Células-Tronco Neoplásicas/metabolismoRESUMO
BACKGROUND: Arterial thrombosis is a serious and rare complication of ovarian hyperstimulation syndrome (OHSS). Herein, we describe a case of OHSS complicated by common carotid artery thrombosis and malignant middle cerebral artery infarction after egg retrieval and before embryo transfer. CASE SUMMARY: A 32-year-old female with a family history of thrombosis who was undergoing in vitro fertilization due to unexplained infertility, was admitted due to abdominal distension for 3 d and coma for 2 h. She received egg retrieval 7 d ago and embryo transfer had not yet been performed. Blood biochemical analysis showed estrogen of 15781 pmol/L. Gynecological examination showed palpable masses on both sides of the adnexal areas. Ultrasound observed enlarged ovaries and abdominal ascites. Imaging examination of the head and neck revealed fresh malignant middle cerebral artery infarction in the left side of brain and internal carotid artery as well as occlusion in the left carotid artery, internal carotid artery, and middle cerebral artery. The patient was finally diagnosed with severe OHSS, complicated by common carotid artery thrombosis and malignant middle cerebral artery infarction. Liquid replacement, anticoagulation, vascular endothelium protection, brain protection and decompressive craniectomy were carried out. Rehabilitation training was then performed for 6 mo. At present, she has poor speaking ability and decreased muscle strength on the right side. CONCLUSION: There is a risk of thrombosis during any period of OHSS. During in vitro assisted reproduction, for cases with a family history of thrombosis, hyperlipidemia and other high-risk factors, serum lipid levels should be controlled as soon as possible to improve metabolic dysfunction. When thrombosis occurs, timely and effective treatment should be performed to improve the prognosis.
RESUMO
Fatty acid oxidation dependency of leukemia cells has been documented in recent studies. Pharmacologic inhibition of fatty acid oxidation, thereby, displays significant effects in suppressing leukemia. 2-Bromopalmitate, a palmitate analogue, was initially identified as an inhibitor of fatty acid oxidation, and recently recognized as an inhibitor of protein palmitoylation. However, the effects of 2-Bromopalmitate on leukemia and its cellular targets remain obscure. Herein, we discover in cultured cell lines, a transplantable mouse model, and primary blasts that 2-Bromopalmitate presents synergistic differentiation induction with all-trans retinoic acid in acute promyelocytic leukemia. Moreover, 2-Bromopalmitate overcomes all-trans retinoic acid resistance in all-trans retinoic acid-resistant cells and leukemic mice. Mechanistically, 2-Bromopalmitate covalently binds at cysteine 105 and cysteine 174 of retinoic acid receptor alpha (RARα) and stabilizes RARα protein in the presence of all-trans retinoic acid which is known to induce RARα degradation, leading to enhanced transcription of RARα-target genes. Mutation of both cysteines largely abrogates the synergistic effect of 2-Bromopalmitate on all-trans retinoic acid-induced differentiation, demonstrating that 2-Bromopalmitate promotes all-trans retinoic acid-induced differentiation through binding RARα. All-trans retinoic acid-based regimens including arsenic trioxide or chemotherapy, as preferred therapy for acute promyelocytic leukemia, induce adverse events and irreversible resistance. We expect that combining all-trans retinoic acid with 2-Bromopalmitate would be a promising therapeutic strategy for acute promyelocytic leukemia, especially for overcoming all-trans retinoic acid resistance of relapsed acute promyelocytic leukemia patients.
Assuntos
Sistemas de Liberação de Medicamentos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Leucemia Promielocítica Aguda/tratamento farmacológico , Proteínas de Neoplasias/agonistas , Palmitatos/farmacologia , Receptor alfa de Ácido Retinoico/agonistas , Tretinoína/farmacologia , Humanos , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/patologia , Proteínas de Neoplasias/metabolismo , Receptor alfa de Ácido Retinoico/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
MicroRNA (miRNA) is involved in the progression and metastasis of diverse human cancers, including breast cancer, as strong evidence has been found that miRNAs can act as oncogenes or tumor suppressor genes. Here, we show that miR-494 is decreased in human breast cancer specimens and breast cancer cell lines. Ectopic expression of miR-494 in basal-like breast cancer cell lines MDA-MB-231-LUC-D2H3LN and BT-549 inhibits clonogenic ability and metastasis-relevant traits in vitro. Moreover, ectopic expression of miR-494 suppresses neoplasm initiation as well as pulmonary metastasis in vivo. Further studies have identified PAK1, as a direct target gene of miR-494, contributes to the functions of miR-494. Remarkably, the expression of PAK1 is inversely correlated with the level of miR-494 in human breast cancer samples. Furthermore, re-expression of PAK1 partially reverses miR-494-mediated proliferative and clonogenic inhibition as well as migration and invasion suppression in breast cancer cells. Taken together, these findings highlight an important role for miR-494 in the regulation of progression and metastatic potential of breast cancer and suggest a potential application of miR-494 in breast cancer treatment.
Assuntos
Neoplasias da Mama/genética , Carcinogênese/genética , Neoplasias Pulmonares/genética , MicroRNAs/genética , Quinases Ativadas por p21/genética , Animais , Neoplasias da Mama/patologia , Proliferação de Células/genética , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Células MCF-7 , Camundongos , MicroRNAs/biossíntese , MicroRNAs/metabolismo , Invasividade Neoplásica/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Quinases Ativadas por p21/metabolismoAssuntos
Proteínas de Transporte/genética , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Leucemia Mieloide Aguda/genética , Proteínas de Membrana/genética , Proteínas de Fusão Oncogênica/metabolismo , Proteína 1 Parceira de Translocação de RUNX1/metabolismo , Hormônios Tireóideos/genética , Translocação Genética , Animais , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Cromossomos Humanos Par 21 , Cromossomos Humanos Par 8 , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Modelos Animais de Doenças , Regulação Leucêmica da Expressão Gênica , Humanos , Leucemia Mieloide Aguda/diagnóstico , Proteínas de Membrana/metabolismo , Camundongos , Mutação , Proteínas de Fusão Oncogênica/genética , Ligação Proteica , Proteína 1 Parceira de Translocação de RUNX1/genética , Elementos de Resposta , Hormônios Tireóideos/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas de Ligação a Hormônio da TireoideRESUMO
MicroRNAs have been integrated into tumorigenic programs as either oncogenes or tumor suppressor genes. The miR-630 was reported to be deregulated and involved in tumor progression of several human malignancies. However, its expression regulation shows diversity in different kinds of cancers and its potential roles remain greatly elusive. Herein, we demonstrate that miR-630 is significantly suppressed in human breast cancer specimens, as well as in various breast cancer cell lines. In aggressive MDA-MB-231-luc and BT549 breast cancer cells, ectopic expression of miR-630 strongly inhibits cell motility and invasive capacity in vitro. Moreover, lentivirus delivered miR-630 bestows MDA-MB-231-luc cells with the ability to suppress cell colony formation in vitro and pulmonary metastasis in vivo. Further studies identify metadherin (MTDH) as a direct target gene of miR-630. Functional studies shows that MTDH contributes to miR-630-endowed effects including cell migration and invasion as well as colony formation in vitro. Taken together, these findings highlight an important role for miR-630 in the regulation of metastatic potential of breast cancer and suggest a potential application of miR-630 in breast cancer treatment.
Assuntos
Neoplasias da Mama/genética , Moléculas de Adesão Celular/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Western Blotting , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Moléculas de Adesão Celular/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Movimento Celular/genética , Progressão da Doença , Regulação para Baixo , Feminino , Humanos , Proteínas de Membrana , Camundongos Endogâmicos NOD , Pessoa de Meia-Idade , Invasividade Neoplásica , Metástase Neoplásica , Proteínas de Ligação a RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transplante HeterólogoRESUMO
Cbx4 is a polycomb group protein that is also a SUMO E3 ligase, but its potential roles in tumorigenesis remain to be explored. Here, we report that Cbx4, but not other members of the Cbx family, enhances hypoxia-induced vascular endothelial growth factor (VEGF) expression and angiogenesis in hepatocellular carcinoma (HCC) cells through enhancing HIF-1α sumoylations at K391 and K477 in its two SUMO-interacting motifs-dependent mechanisms and increasing transcriptional activity of HIF-1. The Cbx4 expression is significantly correlated with VEGF expression, angiogenesis, and the overall survival of HCC patients and also in subcutaneously and orthotopically transplanted mice HCC models. Collectively, our findings demonstrate that Cbx4 plays a critical role in tumor angiogenesis by governing HIF-1α protein.
Assuntos
Carcinoma Hepatocelular/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Hepáticas/metabolismo , Neovascularização Patológica/metabolismo , Proteínas do Grupo Polycomb/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Western Blotting , Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/patologia , Imunoprecipitação da Cromatina , Ensaio de Imunoadsorção Enzimática , Regulação Neoplásica da Expressão Gênica/fisiologia , Xenoenxertos , Humanos , Imuno-Histoquímica , Ligases , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/patologia , Camundongos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína SUMO-1/metabolismo , Fator A de Crescimento do Endotélio Vascular/biossínteseRESUMO
Peroxiredoxins (Prx), a family of small non-seleno peroxidases, are important regulators for cellular reactive oxygen species (ROS), which contribute to many signaling pathways and pathogenesis of diseases. Targeting redox homeostasis is being developed as a promising therapeutic strategy for many diseases such as cancers. This mini-review attempts to focus on our recent discoveries on adenanthin as the first natural molecule to specifically target the resolving cysteines of Prx I and Prx II and thus inhibit their peroxidase activities, and its role in differentiation induction in vitro and in vivo of acute myeloid leukemic cells.
Assuntos
Antineoplásicos/farmacologia , Diterpenos/farmacologia , Leucemia/tratamento farmacológico , Leucemia/metabolismo , Peroxirredoxinas/antagonistas & inibidores , Animais , Antineoplásicos/química , Diferenciação Celular/efeitos dos fármacos , Diterpenos/química , Humanos , Leucemia/enzimologia , Leucemia/patologia , Oxirredução/efeitos dos fármacos , Peroxirredoxinas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
MicroRNAs (miRNAs or miR) have been integrated into tumorigenic programs as either oncogenes or tumor suppressor genes. The miR-124 was reported to be attenuated in several tumors, such as glioma, medulloblastoma and hepatocellular carcinoma. However, its role in cancer remains greatly elusive. In this study, we show that the miR-124 expression is significantly suppressed in human breast cancer specimens, which is reversely correlated to histological grade of the cancer. More intriguingly, ectopic expression of miR-124 in aggressive breast cancer cell lines MDA-MB-231 and BT-549 strongly inhibits cell motility and invasive capacity, as well as the epithelial-mesenchymal transition process. Also, lentivirus-delivered miR-124 endows MDA-MB-231 cells with the ability to suppress cell colony formation in vitro and pulmonary metastasis in vivo. Further studies have identified the E-cadherin transcription repressor Slug as a direct target gene of miR-124; its downregulation by miR-124 increases the expression of E-cadherin, a hallmark of epithelial cells and a repressor of cell invasion and metastasis. Moreover, knockdown of Slug notably impairs the motility of MDA-MB-231 cells, whereas re-expression of Slug abrogates the reduction of motility and invasion ability induced by miR-124 in MDA-MB-231 cells. These findings highlight an important role for miR-124 in the regulation of invasive and metastatic potential of breast cancer and suggest a potential application of miR-124 in cancer treatment.
Assuntos
Neoplasias da Mama/patologia , Transição Epitelial-Mesenquimal , Neoplasias Pulmonares/secundário , MicroRNAs/fisiologia , Fatores de Transcrição/genética , Regiões 3' não Traduzidas , Animais , Sequência de Bases , Sítios de Ligação , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Forma Celular , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica , Genes Reporter , Humanos , Luciferases de Renilla/biossíntese , Luciferases de Renilla/genética , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos SCID , MicroRNAs/genética , MicroRNAs/metabolismo , Invasividade Neoplásica , Transplante de Neoplasias , Interferência de RNA , Fatores de Transcrição da Família Snail , Fatores de Transcrição/metabolismo , Fatores de Transcrição/fisiologia , Carga TumoralRESUMO
Peroxiredoxins (Prxs) are potential therapeutic targets for major diseases such as cancers. However, isotype-specific inhibitors remain to be developed. We report that adenanthin, a diterpenoid isolated from the leaves of Rabdosia adenantha, induces differentiation of acute promyelocytic leukemia (APL) cells. We show that adenanthin directly targets the conserved resolving cysteines of Prx I and Prx II and inhibits their peroxidase activities. Consequently, cellular H(2)O(2) is elevated, leading to the activation of extracellular signal-regulated kinases and increased transcription of CCAAT/enhancer-binding protein ß, which contributes to adenanthin-induced differentiation. Adenanthin induces APL-like cell differentiation, represses tumor growth in vivo and prolongs the survival of mouse APL models that are sensitive and resistant to retinoic acid. Thus, adenanthin can serve as what is to our knowledge the first lead natural compound for the development of Prx I- and Prx II-targeted therapeutic agents, which may represent a promising approach to inducing differentiation of APL cells.