RESUMEN
A series of novel tetrazole analogues of resveratrol were synthesized and evaluated for their anti-leukemic activity against an extensive panel of human cancer cell lines and against the MV4-11 AML cell line. These molecules were designed as drug-like derivatives of the resveratrol analogue DMU-212 and its cyano derivatives. Four compounds 8g, 8h, 10a and 10b exhibited LD50 values of 4.60⯵M, 0.02⯵M, 1.46⯵M, and 1.08⯵M, respectively, against MV4-11 leukemia cells. The most potent compounds, 8h and 10b, were also found to be active against an extensive panel of human hematological and solid tumor cell lines; compound 8h was the most potent compound with GI50 values <10â¯nM against more than 90% of the human cancer cell lines in the 60-cell panel. Analogues 8g, 8h, 10a and 10b were also tested for their ability to inhibit the polymerization of tubulin, and compound 8h was found to be the most potent analogue. Molecular modeling studies demonstrated that 8h binds to the colchicine binding site on tubulin. Thus, compound 8h is considered to be a lead druglike molecule from this tetrazole series of compounds.
Asunto(s)
Antineoplásicos/farmacología , Tetrazoles/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Relación Estructura-Actividad , Tetrazoles/síntesis química , Tetrazoles/químicaRESUMEN
Cancer is a major global health problem with large therapeutic challenges. Although substantial progress has been made in cancer therapy, there still remains a need to develop novel and effective treatment strategies to treat several relapsed and refractory cancers. Recently, there has been growing demand for considering organometallics as antineoplastic agents. This review is focused on a group of organometallics, silver N-heterocyclic carbene complexes (SCCs) and their anticancer efficacy in targeting multiple pathways in various in vitro cancer model systems. However, the precise molecular mechanism of SCCs anticancer properties remains unclear. Here, we discuss the SCCs chemistry, potential molecular targets, possible molecular mechanism of action, and their application in cancer therapies.
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Antineoplásicos , Complejos de Coordinación , Metano/análogos & derivados , Plata , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Complejos de Coordinación/farmacología , Complejos de Coordinación/uso terapéutico , Humanos , Metano/farmacología , Metano/uso terapéutico , Neoplasias/tratamiento farmacológico , Plata/farmacología , Plata/uso terapéuticoRESUMEN
In the present study, we have designed and synthesized a series of 1-benzyl-2-methyl-3-indolylmethylene barbituric acid analogs (7a-7h) and 1-benzyl-2-methyl-3-indolylmethylene thiobarbituric acid analogs (7 i-7 l) as nucleophosmin 1 (NPM1) inhibitors and have evaluated them for their anti-cancer activity against a panel of 60 different human cancer cell lines. Among these analogs 7 i, 7 j, and 7 k demonstrated potent growth inhibitory effects in various cancer cell types with GI50 values <2 µM. Compound 7 k exhibited growth inhibitory effects on a sub-panel of six leukemia cell lines with GI50 values in the range 0.22-0.35 µM. Analog 7 i also exhibited GI50 values <0.35 µM against three of the leukemia cell lines in the sub-panel. Analogs 7 i, 7 j, 7 k and 7 l were also evaluated against the mutant NPM1 expressing OCI-AML3 cell line and compounds 7 k and 7 l were found to cause dose-dependent apoptosis (AP50 = 1.75 µM and 3.3 µM, respectively). Compound 7k also exhibited potent growth inhibition against a wide variety of solid tumor cell lines: that is, A498 renal cancer (GI50 = 0.19 µM), HOP-92 and NCI-H522 lung cancer (GI50 = 0.25 µM), COLO 205 and HCT-116 colon cancer (GI50 = 0.20 and 0.26 µM, respectively), CNS cancer SF-539 (GI50 = 0.22 µM), melanoma MDA-MB-435 (GI50 = 0.22 µM), and breast cancer HS 578T (GI50 = 0.22 µM) cell lines. Molecular docking studies suggest that compounds 7 k and 7 l exert their anti-leukemic activity by binding to a pocket in the central channel of the NPM1 pentameric structure. These results indicate that the small molecule inhibitors 7 i, 7 j, 7 k, and 7 l could be potentially developed into anti-NPM1 drugs for the treatment of a variety of hematologic malignancies and solid tumors.
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Antineoplásicos/química , Barbitúricos/química , Proteínas Nucleares/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Barbitúricos/síntesis química , Barbitúricos/farmacología , Sitios de Unión , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Simulación del Acoplamiento Molecular , Proteínas Nucleares/metabolismo , Nucleofosmina , Estructura Terciaria de ProteínaRESUMEN
The cell cycle comprises sequential events during which a cell duplicates its genome and divides it into two daughter cells. This process is tightly regulated to ensure that the daughter cell receives identical copied chromosomal DNA and that any errors in the DNA during replication are correctly repaired. Cyclins and their enzyme partners, cyclin-dependent kinases (CDKs), are critical regulators of G- to M-phase transitions during the cell cycle. Mitogenic signals induce the formation of the cyclin/CDK complexes, resulting in phosphorylation and activation of the CDKs. Once activated, cyclin/CDK complexes phosphorylate specific substrates that drive the cell cycle forward. The sequential activation and inactivation of cyclin-CDK complexes are tightly controlled by activating and inactivating phosphorylation events induced by cell-cycle proteins. The non-coding RNAs (ncRNAs), which do not code for proteins, regulate cell-cycle proteins at the transcriptional and translational levels, thereby controlling their expression at different cell-cycle phases. Deregulation of ncRNAs can cause abnormal expression patterns of cell-cycle-regulating proteins, resulting in abnormalities in cell-cycle regulation and cancer development. This review explores how ncRNA dysregulation can disrupt cell division balance and discusses potential therapeutic approaches targeting these ncRNAs to control cell-cycle events in cancer treatment.
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Nucleophosmin 1 (NPM1) is an oligomeric, nucleolar phosphoprotein that functions as a molecular chaperone for both proteins and nucleic acids. NPM1 is mutated in approximately one-third of patients with AML. The mutant NPM1c+ contains a 4-base insert that results in extra C-terminal residues encoding a nuclear export signal, which causes NPM1c+ to be localized in the cytoplasm. Here, we determined the effects of targeting NPM1 in cultured and primary AML cells. Treatment with siRNA to NPM1 induced p53 and p21, decreased the percentage of cells in S-phase of the cell cycle, as well as induced differentiation of the AML OCI-AML3 cells that express both NPMc+ and unmutated NPM1. Notably, knockdown of NPM1 by shRNA abolished lethal AML phenotype induced by OCI-AML3 cells in NOD/SCID mice. Knockdown of NPM1 also sensitized OCI-AML3 to all-trans retinoic acid (ATRA) and cytarabine. Inhibition of NPM1 oligomerization by NSC348884 induced apoptosis and sensitized OCI-AML3 and primary AML cells expressing NPM1c+ to ATRA. This effect was significantly less in AML cells coexpressing FLT3-ITD, or in AML or normal CD34+ progenitor cells expressing wild-type NPM1. Thus, attenuating levels or oligomerization of NPM1 selectively induces apoptosis and sensitizes NPM1c+ expressing AML cells to treatment with ATRA and cytarabine.
Asunto(s)
Antineoplásicos/farmacología , Diferenciación Celular/efectos de los fármacos , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Nucleares/fisiología , Animales , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Sinergismo Farmacológico , Femenino , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Células HL-60 , Humanos , Leucemia Mieloide Aguda/metabolismo , Ratones , Ratones Endogámicos NOD , Ratones SCID , Proteínas Mutantes/metabolismo , Proteínas Mutantes/fisiología , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Nucleofosmina , Multimerización de Proteína/efectos de los fármacos , Multimerización de Proteína/fisiología , ARN Interferente Pequeño/farmacología , Células U937 , Regulación hacia Arriba/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
We systematically evaluated the primary and secondary endpoints used in acute myeloid leukemia (AML) phase III randomized controlled trials (RCTs). We included 238 phase III AML RCTs in the past 15 years that reported 279 primary endpoints and 657 secondary endpoints. Overall survival (OS), progression-free survival (PFS), event-free survival (EFS), and complete remission (CR) were primary endpoints in 120 (43%), 34 (12%), 30 (11%), and 41 (15%) studies, respectively. OS (12.5%), PFS (13.2%), CR (14%), safety (11%), and EFS (9%) were commonly reported secondary endpoints. Among primary endpoints, a higher use of OS (OR 2.03, 95%CI 1.10-3.75, p = 0.023) and lower use of PFS (OR 0.25, 95%CI 0.12-0.52, p < 0.001) was observed from 2014 to 2021 compared to 2006-2013; CR was frequently used in relapsed/refractory compared to frontline RCTs (OR 2.20, 95%CI 1.11-4.38, p = 0.025); EFS was frequently used in frontline compared to relapsed/refractory AML RCTs (OR 10.11, 95%CI 1.34-76.34, p = 0.025). A higher trend in the use of clinically meaningful and objective endpoint of OS over the last 15 years.
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Leucemia Mieloide Aguda , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/tratamiento farmacológico , Inducción de Remisión , Protocolos de Quimioterapia Combinada AntineoplásicaRESUMEN
We investigated the outcomes after Coronavirus disease 2019 (COVID) in hematopoietic cell transplant (HCT) or chimeric antigen receptor-T cell (CART) therapy recipients in a single-centre study including all (n = 261)HCT/CART recipients (allogeneic-HCT 49%, autologous-HCT 40%, CART 11%). The median age was 60 (22-80) years. COVID severity was mild (74%), moderate (11%), and severe/critical (16%) with a mortality rate of 7% and a median duration of infection of 5.7 weeks. Significant predictors of COVID severe disease or mortality included concurrent infection (HR 14.9, 95% CI 2.2-5.6) and immunosuppressive therapy (OR 4.8, 95% CI 1.2-3.4).HCT/CART recipients have a higher risk of mortality with COVID and warrant vigilant interventions.
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COVID-19 , Trasplante de Células Madre Hematopoyéticas , Humanos , Persona de Mediana Edad , COVID-19/epidemiología , COVID-19/terapia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Pandemias , SARS-CoV-2 , Trasplante Homólogo , Receptores de TrasplantesRESUMEN
Aurora kinases (AKs) regulate multiple components of mitotic cell division in eukaryotic cells. Aurora A is frequently amplified or overexpressed in breast cancer cells leading to aberrant chromosome segregation, genomic instability, and activation of oncogenic pathways. In the present studies, we determined the effects of treatment with the pan-AK inhibitor MK-0457 and/or the pan-histone deacetylase inhibitor vorinostat against human breast cancer cells that were either ER-, PR-, and HER2- (MDA-MB-468 and MDA-MB-231) or exhibited Aurora A amplification (BT-474 and MDA-MB-231 cells). Treatment with MK-0457 depleted p-AKs levels and their activity, as well as induced G2/M accumulation, DNA endoreduplication, multipolar mitotic spindles, and apoptosis of the breast cancer cells. Similar apoptotic effects were observed with treatment with the Aurora A-specific inhibitor, MLN8237. Treatment with vorinostat induced hsp90 acetylation and inhibited its chaperone association with AKs, leading to depletion of AKs and Survivin. Exposure of the siRNA to AK A also induced apoptosis, which was augmented by co-treatment with MK-0457 and vorinostat. Co-treatment with vorinostat enhanced MK-0457-mediated inhibition of the activities of Aurora A and Aurora B, leading to synergistic in vitro activity against human breast cancer cells. Co-treatment with MK-0457 and vorinostat also caused greater tumor growth inhibition and superior survival of mice bearing MDA-MB-231 xenografts. These pre-clinical findings indicate that combined treatment with a pan-AK inhibitor or an Aurora A-specific inhibitor and vorinostat represents a novel therapeutic strategy for the treatment of Aurora A-amplified and/or triple negative breast cancers.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apoptosis/efectos de los fármacos , Aurora Quinasa A , Aurora Quinasa B , Aurora Quinasas , Neoplasias de la Mama/enzimología , Línea Celular Tumoral , Sinergismo Farmacológico , Femenino , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Dosificación de Gen , Expresión Génica , Técnicas de Silenciamiento del Gen , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Ácidos Hidroxámicos/administración & dosificación , Proteínas Inhibidoras de la Apoptosis/metabolismo , Ratones , Ratones Endogámicos NOD , Ratones SCID , Piperazinas/administración & dosificación , Unión Proteica , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Interferencia de ARN , Survivin , Vorinostat , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Stromal cell derived factor-1 (SDF-1 or CXCL12) and its receptor CXCR4 are involved in the directional homing to the bone marrow niches and in peripheral mobilization of normal and transformed hematopoietic stem and myeloid progenitor cells. Elevated CXCR4 expression confers poor prognosis, whereas inhibition of CXCR4 signaling overcomes stroma-mediated chemoresistance in acute myeloid leukemia (AML). Here, we demonstrate that treatment with the pan-histone deacetylase inhibitor panobinostat (PS) depleted the mRNA and protein levels of CXCR4 in the cultured and primary AML cells. PS-induced acetylation of the heat shock protein (hsp) 90 reduced the chaperone association between CXCR4 and hsp90, directing CXCR4 to degradation by the 20S proteasome. PS treatment also depleted G protein-coupled receptor kinase 3, as well as attenuated the phosphorylation of AKT and ERK1/2 in AML cells, which was not affected by cotreatment with CXCL12. Compared with each agent alone, cotreatment with PS and CXCR4 antagonist AMD3100 or FC-131 synergistically induced apoptosis of cultured and primary AML cells. PS and FC-131 exerted more lethal effects on primary AML versus normal CD34(+) bone marrow progenitor cells. These findings support the rationale to test the in vivo efficacy of PS in enhancing the lethal effects of CXCR4 antagonists against AML cells.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Ácidos Hidroxámicos/farmacología , Leucemia Mieloide Aguda/tratamiento farmacológico , Receptores CXCR4/antagonistas & inhibidores , Apoptosis/efectos de los fármacos , Bencilaminas , Ciclamas , Sinergismo Farmacológico , Compuestos Heterocíclicos/farmacología , Inhibidores de Histona Desacetilasas , Humanos , Ácidos Hidroxámicos/uso terapéutico , Indoles , Panobinostat , Péptidos Cíclicos/farmacología , ARN Mensajero/antagonistas & inhibidores , Receptores CXCR4/genética , Transducción de Señal/efectos de los fármacos , Células Tumorales CultivadasRESUMEN
Papillary thyroid carcinoma (PTC) demonstrates significantly reduced patient survival with metastatic progression. Tumor progression can be influenced by metabolism, including antioxidant glutathione (GSH). Glutathione peroxidase 4 (GPX4) is a selenoenzyme that uses GSH as a co-factor to regulate lipid peroxidation of cell membranes during increased oxidative stress. GPX4 suppression in tumor cells can induce ferroptosis. This study aims to examine ferroptosis as a potentially critical pathway in effective targeting of thyroid cancer (TC) cells. We treated human TC cells (K1, MDA-T68, MDA-T32, TPC1) with (1S,3R)-RSL3 (RSL3), a small-molecule inhibitor of GPX4 and examined the effects on ferroptosis, tumor cell survival and migration, spheroid formation, oxidative stress, DNA damage repair response, and mTOR signaling pathway in vitro. GPX4 inhibition activated ferroptosis, inducing TC cell death, rapid rise in reactive oxygen species and effectively arrested cell migration in vitro. Suppression of mTOR signaling pathway triggered autophagy. GPX4 genetic knockdown mirrored RSL3 effect on mTOR pathway suppression. RSL3 subdued DNA damage repair response by suppressing phosphorylation of nucleophosmin 1 (NPM1). Thus, observed potent induction of ferroptosis, GPX4-dependent novel suppression of mTOR pathway and DNA damage repair response in preclinical in vitro model of TC supports GPX4 targeting for therapeutic benefit in advanced therapy-resistant thyroid cancers.
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Ferroptosis , Neoplasias de la Tiroides , Humanos , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Muerte Celular , Glutatión Peroxidasa/metabolismo , Glutatión/metabolismo , Neoplasias de la Tiroides/tratamiento farmacológico , Serina-Treonina Quinasas TORRESUMEN
We conducted a systematic review and meta-analysis to evaluate outcomes after allogeneic hematopoietic stem cell transplantation (HSCT) in TP53-mutated acute myeloid leukemia (AML). We performed a literature search on PubMed, Embase, Cochrane Library, and ClinicalTrials.gov. After screening 592 manuscripts, eight studies were included. Data were extracted following Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Pooled analysis was done using the meta-package by Schwarzer et al. Proportions with 95% confidence intervals (CIs) were computed. We analyzed 297 patients. The median follow-up was 45 (0.9-407.3) months. The pooled 2-year overall survival was 29.7% (95% CI 0.17-0.43, n = 82/248). The pooled relapse rate was 61.4% (95% CI 0.41-0.79, n = 139/247) at a median follow-up time of 2 (0.26-3) years. Three-year progression-free survival and non-relapse mortality were reported by one study as 7.5% and 32.5%, respectively. Outcomes of HSCT for TP53-mutated AML are poor; however, HSCT confers a survival advantage as compared to non-transplant palliative therapies.
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Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Humanos , Trasplante Homólogo , Enfermedad Crónica , Supervivencia sin Progresión , Recurrencia , Estudios Retrospectivos , Proteína p53 Supresora de TumorRESUMEN
Gene fusions are known to drive many human cancers. Therefore, the functional characterization of newly discovered fusions is critical to understanding the oncobiology of these tumors and to enable therapeutic development. NPM1-TYK2 is a novel fusion identified in CD30 + lymphoproliferative disorders, and here we present the functional evaluation of this fusion gene as an oncogene. The chimeric protein consists of the amino-terminus of nucleophosmin 1 (NPM1) and the carboxyl-terminus of tyrosine kinase 2 (TYK2), including the kinase domain. Using in vitro lymphoid cell transformation assays and in vivo tumorigenic xenograft models we present direct evidence that the fusion gene is an oncogene. NPM1 fusion partner provides the critical homodimerization needed for the fusion kinase constitutive activation and downstream signaling that are responsible for cell transformation. As a result, our studies identify NPM1-TYK2 as a novel fusion oncogene and suggest that inhibition of fusion homodimerization could be a precision therapeutic approach in cutaneous T-cell lymphoma patients expressing this chimera.
RESUMEN
Background: Natural killer (NK) cells play a vital role in early immune reconstitution following allogeneic hematopoietic stem cell transplantation (HSCT). Methods: A literature search was performed on PubMed, Cochrane, and Clinical trials.gov through April 20, 2022. We included 21 studies reporting data on the impact of NK cells on outcomes after HSCT. Data was extracted following the PRISMA guidelines. Pooled analysis was done using the meta-package (Schwarzer et al.). Proportions with 95% confidence intervals (CI) were computed. Results: We included 1785 patients from 21 studies investigating the impact of NK cell reconstitution post-HSCT (8 studies/1455 patients), stem cell graft NK cell content (4 studies/185 patients), therapeutic NK cell infusions post-HSCT (5 studies/74 patients), and pre-emptive/prophylactic NK cell infusions post-HSCT (4 studies/77 patients). Higher NK cell reconstitution was associated with a better 2-year overall survival (OS) (high: 77%, 95%CI 0.73-0.82 vs low: 55%, 95%CI 0.37-0.72; n=899), however, pooled analysis for relapse rate (RR) or graft versus host disease (GVHD) could not be performed due to insufficient data. Higher graft NK cell content demonstrated a trend towards a better pooled OS (high: 65.2%, 95%CI 0.47-0.81 vs low: 46.5%, 95%CI 0.24-0.70; n=157), lower RR (high: 16.9%, 95%CI 0.10-0.25 vs low: 33%, 95%CI 0.04-0.72; n=157), and lower acute GVHD incidence (high: 27.6%, 95%CI 0.20-0.36 vs low: 49.7%, 95%CI 0.26-0.74; n=157). Therapeutic NK or cytokine-induced killer (CIK) cell infusions for hematologic relapse post-HSCT reported an overall response rate (ORR) and complete response (CR) of 48.9% and 11% with CIK cell infusions and 82.8% and 44.8% with NK cell infusions, respectively. RR, acute GVHD, and chronic GVHD were observed in 55.6% and 51.7%, 34.5% and 20%, and 20.7% and 11.1% of patients with CIK and NK cell infusions, respectively. Pre-emptive donor-derived NK cell infusions to prevent relapse post-HSCT had promising outcomes with 1-year OS of 69%, CR rate of 42%, ORR of 77%, RR of 28%, and acute and chronic GVHD rates of 24.9% and 3.7%, respectively. Conclusion: NK cells have a favorable impact on outcomes after HSCT. The optimal use of NK cell infusions post-HSCT may be in a pre-emptive fashion to prevent disease relapse.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Humanos , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Células Asesinas Naturales , Recurrencia , CitocinasRESUMEN
We present a systematic review and meta-analysis to evaluate outcomes after venetoclax (VEN) with hypomethylating agents (HMA) in myelodysplastic syndromes (MDS). We performed a literature search on PubMed, Cochrane Library, EMBASE, and Clinicaltrials.gov. After screening 2004 manuscripts, 16 studies were included. Data was extracted following PRISMA guidelines. Pooled analysis was done using the meta-package by Schwarzer et al. Proportions with 95% confidence intervals (CI) were computed. We analyzed the outcomes of 373 patients from 11 retrospective studies and five phase 1 b clinical trials. Pooled complete response with or without hematological recovery was 60% (95% CI 0.49-0.7, I2= 67%, n = 373). Hematopoietic cell transplantation was performed in 32% of patients (95% CI 0.2-0.46, I2= 62%, n = 187). Overall mortality was 45% (95% CI 0.31-0.59, I2=54%, n = 140). VEN-HMA combination therapy demonstrated promising outcomes in MDS. Prospective randomized data is needed to ascertain the benefit of VEN and its impact in MDS patients.
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Antimetabolitos Antineoplásicos , Síndromes Mielodisplásicos , Humanos , Estudios Retrospectivos , Estudios Prospectivos , Antimetabolitos Antineoplásicos/uso terapéuticoRESUMEN
The polycomb repressive complex (PRC) 2 contains 3 core proteins, EZH2, SUZ12, and EED, in which the SET (suppressor of variegation-enhancer of zeste-trithorax) domain of EZH2 mediates the histone methyltransferase activity. This induces trimethylation of lysine 27 on histone H3, regulates the expression of HOX genes, and promotes proliferation and aggressiveness of neoplastic cells. In this study, we demonstrate that treatment with the S-adenosylhomocysteine hydrolase inhibitor 3-deazaneplanocin A (DZNep) depletes EZH2 levels, and inhibits trimethylation of lysine 27 on histone H3 in the cultured human acute myeloid leukemia (AML) HL-60 and OCI-AML3 cells and in primary AML cells. DZNep treatment induced p16, p21, p27, and FBXO32 while depleting cyclin E and HOXA9 levels. Similar findings were observed after treatment with small interfering RNA to EZH2. In addition, DZNep treatment induced apoptosis in cultured and primary AML cells. Furthermore, compared with treatment with each agent alone, cotreatment with DZNep and the pan-histone deacetylase inhibitor panobinostat caused more depletion of EZH2, induced more apoptosis of AML, but not normal CD34(+) bone marrow progenitor cells, and significantly improved survival of nonobese diabetic/severe combined immunodeficiency mice with HL-60 leukemia. These findings indicate that the combination of DZNep and panobinostat is effective and relatively selective epigenetic therapy against AML cells.
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Adenosina/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Proteínas de Unión al ADN/antagonistas & inhibidores , Epigénesis Genética/efectos de los fármacos , Ácidos Hidroxámicos/administración & dosificación , Leucemia Mieloide Aguda/tratamiento farmacológico , Factores de Transcripción/antagonistas & inhibidores , Adenosina/administración & dosificación , Apoptosis/efectos de los fármacos , Proteínas Portadoras/metabolismo , Ciclo Celular/efectos de los fármacos , Proteínas de Unión al ADN/metabolismo , Evaluación Preclínica de Medicamentos , Proteína Potenciadora del Homólogo Zeste 2 , Inhibidores Enzimáticos/administración & dosificación , Células HL-60 , Inhibidores de Histona Desacetilasas , Histona Metiltransferasas , N-Metiltransferasa de Histona-Lisina/antagonistas & inhibidores , Histonas/química , Histonas/metabolismo , Humanos , Indoles , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Proteínas de Neoplasias , Proteínas Nucleares/metabolismo , Panobinostat , Complejo Represivo Polycomb 2 , Factores de Transcripción/metabolismo , Resultado del Tratamiento , Células Tumorales CultivadasRESUMEN
Pan-histone deacetylase inhibitors, for example, vorinostat and panobinostat (LBH589; Novartis Pharmaceuticals, East Hanover, NJ), have shown clinical efficacy against advanced cutaneous T-cell lymphoma (CTCL). However, the molecular basis of this activity remains unclear. HDAC7, a class IIA histone deacetylase (HDAC), is overexpressed in thymocytes, where it represses expression of the proapoptotic nuclear orphan receptor Nur77. Here, we demonstrate that treatment with panobinostat rapidly inhibits the in vitro and intracellular activity, as well as the mRNA and protein levels of HDAC7, and induces expression and translocation of Nur77 to the mitochondria. There, Nur77 converts death resistance protein Bcl-2 into a killer protein, promoting cell death of cultured and patient-derived human CTCL cells. Treatment with panobinostat improved survival of athymic nude mice implanted with human CTCL cells. Ectopic expression of Nur77 induced apoptosis and sensitized HH cells to panobinostat, whereas combined knockdown of Nur77 and its family member Nor1 was necessary to inhibit panobinostat-induced apoptosis of CTCL cells. Cotreatment with the Bcl-2/Bcl-x(L) antagonist ABT-737 decreased resistance and synergistically induced apoptosis of human CTCL cells. These findings mechanistically implicate HDAC7 and Nur77 in sensitizing human CTCL cells to panobinostat as well as suggest that cotreatment with an anti-Bcl-2 agent would augment the anti-CTCL activity of panobinostat.
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Compuestos de Bifenilo/farmacología , Proteínas de Unión al ADN/metabolismo , Histona Desacetilasas/metabolismo , Ácidos Hidroxámicos/farmacología , Linfoma Cutáneo de Células T/metabolismo , Linfoma Cutáneo de Células T/patología , Nitrofenoles/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Receptores de Esteroides/metabolismo , Sulfonamidas/farmacología , Transporte Activo de Núcleo Celular , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proteínas de Unión al ADN/genética , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Histona Desacetilasas/genética , Humanos , Indoles , Linfoma Cutáneo de Células T/genética , Proteínas de Transporte de Membrana/genética , Proteínas de Transporte de Membrana/metabolismo , Ratones , Ratones Desnudos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares , Panobinostat , Piperazinas/farmacología , Regiones Promotoras Genéticas/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Interferencia de ARN , Receptores de Esteroides/genética , Especificidad por Sustrato , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The mutant JAK2V617F tyrosine kinase (TK) is present in the majority of patients with BCR-ABL-negative myeloproliferative neoplasms (MPNs). JAK2V617F activates downstream signaling through the signal transducers and activators of transcription (STAT), RAS/mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3 (PI3)/AKT pathways, conferring proliferative and survival advantages in the MPN hematopoietic progenitor cells (HPCs). Treatment with the pan-histone deacetylase (HDAC) inhibitor panobinostat (PS) is known to inhibit the chaperone function of heat shock protein 90, as well as induce growth arrest and apoptosis of transformed HPCs. Here, we demonstrate that PS treatment depletes the autophosphorylation, expression, and downstream signaling of JAK2V617F. Treatment with PS also disrupted the chaperone association of JAK2V617F with hsp90, promoting proteasomal degradation of JAK2V617F. PS also induced apoptosis of the cultured JAK2V617F-expressing human erythroleukemia HEL92.1.7 and Ba/F3-JAK2V617F cells. Treatment with the JAK2 TK inhibitor TG101209 attenuated JAK2V617F autophosphorylation and induced apoptosis of HEL92.1.7 and Ba/F3-JAK2V617F cells. Cotreatment with PS and TG101209 further depleted JAK/STAT signaling and synergistically induced apoptosis of HEL92.1.7 and Ba/F3-JAK2V617F cells. Cotreatment with TG101209 and PS exerted greater cytotoxicity against primary CD34(+) MPN cells than normal CD34(+) HPCs. These in vitro findings suggest combination therapy with HDAC and JAK2V617F inhibitors is of potential value for the treatment of JAK2V617F-positive MPN.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Células Madre Hematopoyéticas/efectos de los fármacos , Trastornos Linfoproliferativos/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Animales , Apoptosis , Western Blotting , Sinergismo Farmacológico , Inhibidores Enzimáticos/administración & dosificación , Expresión Génica/efectos de los fármacos , Células Madre Hematopoyéticas/metabolismo , Humanos , Ácidos Hidroxámicos/administración & dosificación , Inmunoprecipitación , Indoles , Janus Quinasa 2/metabolismo , Ratones , Panobinostat , Fosforilación , Reacción en Cadena de la Polimerasa , Pirimidinas/administración & dosificación , Sulfonamidas/administración & dosificaciónRESUMEN
Anaplastic large cell lymphoma (ALCL) is an aggressive type of non-Hodgkin lymphoma. More than three-fourths of anaplastic lymphoma kinase (ALK)-positive ALCL cases express the nucleophosmin 1 (NPM1)-ALK fusion gene as a result of t(2;5) chromosomal translocation. The homodimerization of NPM1-ALK fusion protein mediates constitutive activation of the chimeric tyrosine kinase activity and downstream signaling pathways responsible for lymphoma cell proliferation and survival. Gilteritinib is a tyrosine kinase inhibitor recently approved by the FDA for the treatment of FMS-like tyrosine kinase mutation-positive acute myeloid leukemia. In this study, we demonstrate for the first time gilteritinib-mediated growth inhibitory effects on NPM1-ALK-driven ALCL cells. We utilized a total of five ALCL model cell lines, including both human and murine. Gilteritinib treatment inhibits NPM1-ALK fusion kinase phosphorylation and downstream signaling, resulting in induced apoptosis. Gilteritinib-mediated apoptosis was associated with caspase 3/9, PARP cleavage, the increased expression of proapoptotic protein BAD, and decreased expression of antiapoptotic proteins, survivin and MCL-1. We also found downregulation of fusion kinase activity resulted in decreased c-Myc protein levels. Furthermore, cell-cycle analysis indicated gilteritinib induced G0-G1-phase cell-cycle arrest and reduced CD30 expression. In summary, our preclinical studies explored the novel therapeutic potential of gilteritinib in the treatment of ALCL cells expressing NPM1-ALK and potentially in other ALK or ALK fusion-driven hematologic or solid malignancies. IMPLICATIONS: Our preclinical results explore the use of gilteritinib for the treatment of NPM1-ALK-driven ALCL cells and pave a path for developing future clinical trials. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/19/5/913/F1.large.jpg.
Asunto(s)
Quinasa de Linfoma Anaplásico/metabolismo , Compuestos de Anilina/uso terapéutico , Linfoma Anaplásico de Células Grandes/tratamiento farmacológico , Pirazinas/uso terapéutico , Compuestos de Anilina/farmacología , Humanos , Linfoma Anaplásico de Células Grandes/genética , Pirazinas/farmacologíaRESUMEN
Poor graft function (PGF) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) characterized by multilineage cytopenia in the absence of mixed donor chimerism (<95% donor), relapse, or severe graft-versus-host disease (GVHD). We present a systemic review and meta-analysis aimed at assessing the outcomes with CD34-selected stem cell boost (SCB) for PGF in adult allo-HSCT recipients. We screened a total of 1753 records identified from 4 databases (PubMed, Embase, Cochrane, and ClinicalTrials.gov) following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, using the search terms "hematological malignancies," "hematopoietic stem cell transplantation," "CD34 antigen(s)," "graft failure," and "poor graft function," from the date of inception to January 2021. After excluding review, duplicate, and nonrelevant articles, we included 7 studies reporting outcomes following administration of CD34-selected SCB for PGF after allo-HSCT, including hematologic complete response (CR) and overall response rate (ORR), GVHD, and overall survival (OS). Quality evaluation was done using the National Institutes of Health quality assessment tool. Pooled analysis was done using the R 'meta' package, and proportions with 95% confidence intervals (CIs) were computed. The inter-study variance was calculated using the Der Simonian-Laird estimator. We identified 209 patients who received CD34-selected SCB for PGF after allo-HSCT. The median age was 49 years (range, 18 to 69 years), and 61% were men. Primary graft sources included peripheral blood stem cells (72%) and bone marrow (28%). Donor types were matched sibling (37%), matched unrelated (36%), mismatched unrelated (22%), and haploidentical donors (5%). The median time from allo-HSCT to SCB was 138 days (range, 113 to 450 days). The median SCB dose was 3.45 × 106 CD34 cells/kg (range, 3.1 to 4.9 × 106 cells/kg). CR and ORR were 72% (95% CI, 63% to 79%; I2 = 26%) and 80% (95% CI, 74% to 85%; I2 = 0%), respectively. After a median follow-up of 42 months (range, 30 to 77 months), the actuarial survival rate was 54% (95% CI, 47% to 61%; I2 = 0%). OS ranged from 80% at 1 year to 40% at 9 years. The incidences of acute and chronic GVHD after SCB were 17% (95% CI, 13% to 23%; I2 = 0%) and 18% (95% CI, 8% to 34%; I2 = 76%), respectively. Nonrelapse mortality was reported in 42 patients, with a pooled rate of 27% (95% CI, 17% to 40; I2 = 59%), and death due to relapse was reported in 25 patients, with a pooled rate of 17% (95% CI, 11% to 23%; I2 = 0%). Our data show that CD34-selected SCB improves outcomes after PGF post allo-HSCT with an acceptable toxicity profile. The literature lacks high-quality randomized evidence, and there remains an unmet need for prospective studies to address the optimal dosing and manipulation of SCB. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.
Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Estudios ProspectivosRESUMEN
Coronavirus disease 2019 (COVID-19), a respiratory illness caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was declared a pandemic in March 2020, and has caused more than 600,000 deaths in the United States at the time of this report. Hematopoietic stem cell transplantation (HCT) or chimeric antigen receptor T cell (CAR-T) therapy recipients have a higher risk of mortality with COVID-19 owing to profound immune dysregulation. In this study, we investigated the impact of SARS-CoV-2 in HCT/CAR-T therapy recipients. This single-center prospective study included all (n = 58) adult HCT/CAR-T recipients who were diagnosed with COVID-19 at the University of Kansas Medical Center between March 2020 and May 2021. Baseline and disease-related characteristics were ascertained from medical records. Data were analyzed using SPSS version 21 (IBM, Armonk, NY). Bivariate analyses, using the chi-square and t-test, and logistic regression analyses were conducted. The study included 58 HCT/CAR-T patients who acquired SARS-CoV-2 infection, including recipients of allogeneic HCT (n = 32), autologous HCT (n = 23), and CAR-T therapy (n = 3). The median patient age was 58 years (range, 24 to 77 years), and 64% were males. The median time from HCT/CAR-T therapy to SARS-CoV-2 infection was 17.7 months (range, 0.2 to 201.9 months), and 22% of the patients acquired SARS-CoV-2 within the first 100 days post-HCT/CAR-T therapy. The primary hematologic disorders were plasma cell (36%), myeloid (38%), and lymphoid (26%) malignancies. Myeloablative conditioning was performed in 62% of patients. Donors were autologous (45%), matched sibling (15%), matched unrelated (21%), and haploidentical (19%). Prior history of grade II-IV acute graft-versus-host disease (GVHD), active GVHD, and current immunosuppressive therapy (IST) was noted in 22%, 31%, and 36% of patients, respectively. Concurrent infections were observed in 19%. Lymphopenia (P = .049) and high serum ferritin concentration (P = .020) were associated with mortality. COVID-19 severity was mild in 50% of the patients, moderate in 22%, and severe in 28%. Clinical findings included pneumonia or abnormal chest imaging (in 50%), hypoxia (28%), intensive care unit admission (19%), and mechanical ventilation (10%). Therapies included remdesivir (in 41%), convalescent plasma (35%), dexamethasone (22%), monoclonal antibodies (19%), and tocilizumab (3%). The median duration of viral shedding (positive SARS-CoV-2 PCR) was 7.7 weeks (range, 2 to 18.7 weeks), and 2 patients had a persistent infection for >5 months post-CAR-T therapy. After a median follow-up of 6.1 months (range, 0.5-13.6 months), the mortality rate was 16% in all patients and 28% in allogeneic HCT recipients. Among 9 patients who died, the median survival after SARS-CoV-2 infection was 23 days (range, 14 to 140 days). In survivors with moderate-severe COVID-19, the median time to recovery was 4.2 weeks (range, 1.1 to 24.7 weeks). Among allogeneic HCT recipients, 5 (16%) developed subsequent pulmonary chronic GVHD necessitating systemic steroids and additional IST. Significant predictors of COVID-19 severity included allogeneic HCT (odds ratio [OR], 3.6, 95% confidence interval [CI], 1.2 to 10.8; P = .020), history of grade II-IV acute GVHD (OR, 4.6; 95% CI, 1.10 to 18.86; P = .036) and concurrent IST (OR, 5.9; 95% CI, 1.8 to 19.8; P = .004). HCT and CAR-T cell therapy recipients are at an increased risk of moderate-severe COVID-19 pneumonia and higher mortality with SARS-CoV-2 infection. Our findings confirm the need for continuing vigilance with social distancing and masks, vaccination prioritization, close monitoring, and aggressive treatment of HCT/CAR-T therapy recipients.