RESUMEN
T-cell acute lymphoblastic leukemia (T-ALL) is a serious hematologic malignancy and glucocorticoid resistance is the main recurrent cause for a high relapsed and death rate. Here, we proposed an effective therapeutic regimen of combining gamma-secretase inhibitors (GSIs) with dexamethasone (DEX) to overcome glucocorticoid resistance. Moreover, the bone marrow targeting DT7 peptide-modified lecithin nanoparticles co-loaded with DEX and GSI (TLnp/D&G) were developed to enhance T-ALL cells recognition and endocytosis. In vitro cytotoxicity studies showed that TLnp/D&G significantly inhibited cell survival and promoted apoptosis of T-ALL cells. Mechanically, we found that GSIs promoted DEX-induced cell apoptosis by two main synergetic mechanisms: 1) GSIs significantly upregulated glucocorticoid receptor (GR) expression in T-ALL and restored the glucocorticoid-induced pro-apoptotic response. 2) Both DEX and GSI synergistically inhibited BCL2 and suppressed the survival of T-ALL cells. Furthermore, in vivo studies demonstrated that TLnp/D&G showed high bone marrow accumulation and better antileukemic efficacy both in leukemia bearing models and in systemic Notch1-induced T-ALL models, with excellent biosafety and reduced gastrointestinal toxicity. Overall, our study provides new strategies for the treatment of T-ALL and promising bone marrow targeting systems with high transformation potential.
Asunto(s)
Nanopartículas , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Apoptosis , Línea Celular Tumoral , Dexametasona/farmacología , Glucocorticoides , Humanos , Lecitinas/farmacología , Lecitinas/uso terapéutico , Errores Innatos del Metabolismo , Péptidos/farmacología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Receptor Notch1/metabolismo , Receptores de Glucocorticoides/deficiencia , Linfocitos T/metabolismoRESUMEN
Despite progress in the treatment of acute lymphoblastic leukemia (ALL), T-cell ALL (T-ALL) has limited treatment options, particularly in the setting of relapsed/refractory disease. Using an unbiased genome-scale CRISPR-Cas9 screen we sought to identify pathway dependencies for T-ALL which could be harnessed for therapy development. Disruption of the one-carbon folate, purine and pyrimidine pathways scored as the top metabolic pathways required for T-ALL proliferation. We used a recently developed inhibitor of SHMT1 and SHMT2, RZ-2994, to characterize the effect of inhibiting these enzymes of the one-carbon folate pathway in T-ALL and found that T-ALL cell lines were differentially sensitive to RZ-2994, with the drug inducing a S/G2 cell cycle arrest. The effects of SHMT1/2 inhibition were rescued by formate supplementation. Loss of both SHMT1 and SHMT2 was necessary for impaired growth and cell cycle arrest, with suppression of both SHMT1 and SHMT2 inhibiting leukemia progression in vivo. RZ-2994 also decreased leukemia burden in vivo and remained effective in the setting of methotrexate resistance in vitro. This study highlights the significance of the one-carbon folate pathway in T-ALL and supports further development of SHMT inhibitors for treatment of T-ALL and other cancers.
Asunto(s)
Sistemas CRISPR-Cas , Resistencia a Antineoplásicos/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Ácido Fólico/metabolismo , Glicina Hidroximetiltransferasa/antagonistas & inhibidores , Metotrexato/farmacología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Animales , Antimetabolitos Antineoplásicos/farmacología , Apoptosis , Ciclo Celular , Proliferación Celular , Femenino , Humanos , Ratones , Ratones Endogámicos NOD , Ratones SCID , Leucemia-Linfoma Linfoblástico de Células T Precursoras/enzimología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Pronóstico , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
USP7, which encodes a deubiquitylating enzyme, is among the most frequently mutated genes in pediatric T-ALL, with somatic heterozygous loss-of-function mutations (haploinsufficiency) predominantly affecting the subgroup that has aberrant TAL1 oncogene activation. Network analysis of > 200 T-ALL transcriptomes linked USP7 haploinsufficiency with decreased activities of E-proteins. E-proteins are also negatively regulated by TAL1, leading to concerted down-regulation of E-protein target genes involved in T-cell development. In T-ALL cell lines, we showed the physical interaction of USP7 with E-proteins and TAL1 by mass spectrometry and ChIP-seq. Haploinsufficient but not complete CRISPR knock-out of USP7 showed accelerated cell growth and validated transcriptional down-regulation of E-protein targets. Our study unveiled the synergistic effect of USP7 haploinsufficiency with aberrant TAL1 activation on T-ALL, implicating USP7 as a haploinsufficient tumor suppressor in T-ALL. Our findings caution against a universal oncogene designation for USP7 while emphasizing the dosage-dependent consequences of USP7 inhibitors currently under development as potential cancer therapeutics.
Asunto(s)
Oncogenes/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Proteína 1 de la Leucemia Linfocítica T Aguda/genética , Peptidasa Específica de Ubiquitina 7/genética , Sistemas CRISPR-Cas/genética , Línea Celular Tumoral , Linaje de la Célula/genética , Proliferación Celular/genética , Regulación Leucémica de la Expresión Génica/genética , Haploinsuficiencia/genética , Humanos , Pediatría , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Activación Transcripcional/genéticaRESUMEN
T-cell lymphoblastic lymphoma (T-LBL) is a heterogeneous malignancy of lymphoblasts committed to T-cell lineage. The dismal outcomes (15%-30%) after T-LBL relapse warrant establishing risk-based treatment. To our knowledge, this study presents the first comprehensive, systematic, integrated, genome-wide analysis including relapsed cases that identifies molecular markers of prognostic relevance for T-LBL. NOTCH1 was identified as the putative driver for T-LBL. An activated NOTCH/PI3K-AKT signaling axis and alterations in cell cycle regulators constitute the core oncogenic program for T-LBL. Mutated KMT2D was identified as a prognostic marker. The cumulative incidence of relapse was 47% ± 17% in patients with KMT2D mutations, compared with 14% ± 3% in wild-type KMT2D. Structural analysis of the mutated domains of KMT2D revealed a plausible impact on structure and functional consequences. These findings provide new insights into the pathogenesis of T-LBL, including high translational potential. The ongoing LBL 2018 trial (www.clinicaltrials.gov #NCT04043494) allows for prospective validation and subsequent fine tuning of the stratification criteria for T-LBL risk groups to improve survival of pediatric patients.
Asunto(s)
Biomarcadores de Tumor/genética , Proteínas de Unión al ADN/genética , Genómica/métodos , Proteínas de Neoplasias/genética , Fosfatidilinositol 3-Quinasas/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Proteínas Proto-Oncogénicas c-akt/genética , Receptor Notch1/genética , Adolescente , Niño , Femenino , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica , Genoma Humano , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Pronóstico , Tasa de SupervivenciaRESUMEN
Allium species are well known plants distributed throughout the world, and they contain various bioactive components with different biological activities including anti-cancer effects. In this study, we investigated the inhibitory effect of Allium senescens L. (A.S.) extract on cell survival and IL-2-mediated inflammation in human T cell acute lymphocytic leukemia (T-ALL) Jurkat cells. Our results showed that A.S. extract induced caspase-dependent apoptosis of Jurkat cells with no significant cytotoxicity in the normal peripheral blood mononuclear cells. A.S. extract induced ROS generation through the activation of MAPK p38 phosphorylation. It also inhibited IL-2 mRNA expression and NF-κB signaling mediated by phorbol 12-myristate 13-acetate, and phytohemagglutinin. Combined treatment with A.S. extract and axitinib/dovitinib exerted enhanced inhibitory effects on T-ALL cell growth and IL-2 production. These results provide novel information on the potential use of A.S. extract as a therapeutic herbal agent for the treatment and prevention of T-ALL.
Asunto(s)
Allium/química , Proliferación Celular/efectos de los fármacos , Inflamación/tratamiento farmacológico , Leucocitos Mononucleares/efectos de los fármacos , Extractos Vegetales/farmacología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Apoptosis , Humanos , Inflamación/metabolismo , Inflamación/patología , Interleucina-2/metabolismo , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/patología , FN-kappa B/metabolismo , Fosforilación , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Transducción de Señal , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
The main active compound of Garcinia hanburyi (referred to as gamboge) is gambogic acid (GA), which has long been a Chinese herbal medicine for treating several types of cancer. However, the potential therapeutic role and mechanisms of GA in Tcell acute lymphoblastic leukemia (TALL) remain unclear. In the present study, the effects of GA on proliferation, cell cycle, apoptosis, and autophagy in TALL cell lines were investigated. The possible mechanisms underlying GA activity were also examined. The results showed that GA inhibited proliferation, induced apoptosis, and activated autophagy in TALL cell lines (Jurkat and Molt4 cells). Findings confirmed that GA has an antileukemia effect against peripheral blood lymphocyte cells in patients with ALL. GA inhibited phosphoGSK3ß S9 (pGSK3ß S9) protein levels to inactivate Wnt signaling and suppress ßcatenin protein levels. In addition, the inhibitory effect of GA on TALL was reversed by overexpression of ßcatenin. Thus, GA can inhibit the growth and survival of TALL cells. GA also had antileukemic activity, at least in part, through the downregulation of the Wnt/ßcatenin signaling pathway.
Asunto(s)
Glucógeno Sintasa Quinasa 3 beta/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Xantonas/farmacología , beta Catenina/genética , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Garcinia cambogia/química , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Medicina Tradicional China/métodos , Fosforilación/efectos de los fármacos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Vía de Señalización Wnt/efectos de los fármacosAsunto(s)
Benzoquinonas/efectos adversos , Enfermedades de la Médula Ósea/inducido químicamente , Médula Ósea/efectos de los fármacos , Nigella sativa , Pancitopenia/inducido químicamente , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Adulto , Benzoquinonas/química , Benzoquinonas/uso terapéutico , Médula Ósea/patología , Enfermedades de la Médula Ósea/patología , Humanos , Masculino , Nigella sativa/química , Pancitopenia/patología , Fitoterapia , Preparaciones de Plantas/efectos adversos , Preparaciones de Plantas/química , Preparaciones de Plantas/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologíaRESUMEN
Since 1970, the isolated and identified components of Brucea javanica (L.) Merr. have been known to contain anticancer effects, particularly antileukemic effect. In this study, the inhibitory effect of Brucea javanica (BJ) on cell growth and inflammation was confirmed in human T-cell acute lymphocytic leukemia (T-ALL) cells, and its efficacy as an antileukemic agent was verified. Our results showed that BJ extract induced caspase-dependent apoptosis of T-ALL Jurkat cells through inhibition of the CK2-mediated signaling pathway, while exerting no significant cytotoxicity in normal peripheral blood mononuclear cells. Moreover, BJ extract suppressed the NF-κB signaling pathway, thus, inhibiting the interleukin (IL)-2 expression induced by phorbol 12-myristate 13-acetate (PMA) and phytohemagglutinin (PHA). Notably, combined treatment with BJ extract plus CX-4945 or imatinib exerted enhanced inhibitory effects on T-ALL cell growth and IL-2 production. Overall, these results suggest that BJ extract can be a potent therapeutic herbal agent for T-ALL treatment and prevention of IL-2 mediated inflammatory immune responses.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Brucea , Proliferación Celular/efectos de los fármacos , Mesilato de Imatinib/farmacología , Inmunosupresores/farmacología , Naftiridinas/farmacología , Extractos Vegetales/farmacología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Apoptosis/efectos de los fármacos , Brucea/química , Quinasa de la Caseína II/metabolismo , Caspasa 3/metabolismo , Caspasa 8/metabolismo , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Inmunosupresores/aislamiento & purificación , Interleucina-2/metabolismo , Células Jurkat , FN-kappa B/metabolismo , Fenazinas , Fosforilación , Fitoterapia , Extractos Vegetales/aislamiento & purificación , Plantas Medicinales , Leucemia-Linfoma Linfoblástico de Células T Precursoras/inmunología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Factores de TiempoRESUMEN
The PI3K/Akt signaling pathway, Notch, and other oncogenes cooperate in the induction of aggressive cancers. Elucidating how the PI3K/Akt pathway facilitates tumorigenesis by other oncogenes may offer opportunities to develop drugs with fewer side effects than those currently available. Here, using an unbiased in vivo chemical genetic screen in Drosophila, we identified compounds that inhibit the activity of proinflammatory enzymes nitric oxide synthase (NOS) and lipoxygenase (LOX) as selective suppressors of Notch-PI3K/Akt cooperative oncogenesis. Tumor silencing of NOS and LOX signaling mirrored the antitumor effect of the hit compounds, demonstrating their participation in Notch-PI3K/Akt-induced tumorigenesis. Oncogenic PI3K/Akt signaling triggered inflammation and immunosuppression via aberrant NOS expression. Accordingly, activated Notch tumorigenesis was fueled by hampering the immune response or by NOS overexpression to mimic a protumorigenic environment. Our lead compound, the LOX inhibitor BW B70C, also selectively killed human leukemic cells by dampening the NOTCH1-PI3K/AKT-eNOS axis.
Asunto(s)
Drosophila melanogaster/metabolismo , Inflamación/patología , Óxido Nítrico/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores Notch/metabolismo , Animales , Carcinogénesis/metabolismo , Catecol Oxidasa/metabolismo , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos , Precursores Enzimáticos/metabolismo , Marcación de Gen , Hemocitos/metabolismo , Humanos , Terapia de Inmunosupresión , Inflamación/inmunología , Lipooxigenasas/metabolismo , Óxido Nítrico Sintasa/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Interferencia de ARN , Reproducibilidad de los Resultados , Transducción de SeñalRESUMEN
Matrine, a natural product extracted from the root of Sophora flavescens, is a promising alternative drug in different types of cancer. Here, we aimed to investigate the therapeutic effects and underlying molecular mechanisms of matrine on human acute lymphoblastic leukemia (ALL) cell line, CCRF-CEM. Cell viability and IC50 values were determined by WST-1 cell cytotoxicity assay. Cell cycle distribution and apoptosis rates were analyzed by flow cytometry. Expression patterns of 44 selected miRNAs and 44 RNAs were analyzed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) using the Applied Biosystems 7500 Fast Real-Time PCR System. Matrine inhibited cell viability and induced apoptosis of CCRF-CEM cells in a dose-dependent manner. Cell cycle analysis demonstrated that matrine-treated CCRF-CEM cells significantly accumulated in the G0/G1 phase compared with the untreated control cells. hsa-miR-376b-3p (-37.09 fold, p = 0.008) and hsa-miR-106b-3p (-16.67 fold, p = 0.028) expressions were decreased, whereas IL6 (95.47 fold, p = 0.000011) and CDKN1A (140.03 fold, p = 0.000159) expressions were increased after matrine treatment. Our results suggest that the downregulation of hsa-miR-106b-3p leads to the upregulation of target p21 gene, CDKN1A, and plays a critical role in the cell cycle progression by arresting matrine-treated cells in the G0/G1 phase.
Asunto(s)
Alcaloides/farmacología , Apoptosis , Puntos de Control del Ciclo Celular , Extractos Vegetales/farmacología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Quinolizinas/farmacología , Antineoplásicos/farmacología , Autofagia , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Fragmentación del ADN , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Fase G1 , Perfilación de la Expresión Génica , Regulación Leucémica de la Expresión Génica , Humanos , Concentración 50 Inhibidora , Interleucina-6/metabolismo , MicroARNs/metabolismo , Raíces de Plantas/química , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Fase de Descanso del Ciclo Celular , Sophora/química , MatrinasRESUMEN
TPD7, a novel biphenyl urea taspine derivative, and berberine have presented inhibition on VEGFR2 that can be regulated by ephrin-B2 reverse signaling through interactions with the PDZ domain. The purpose of this study is to investigate the inhibitory effect of the combination of TPD7 and berberine (TAB) on T-cell acute lymphoblastic leukemia cell growth. TPD7 and berberine together synergistically inhibited the proliferation of Jurkat cells. Also, the combination of TAB induced G1 -phase cell-cycle arrest by downregulating the level of cyclin D1, cyclin E, and CDC2. Furthermore, the combination of TAB significantly enhanced apoptosis in Jurkat cells, and the apoptosis most likely resulted from the modulation of the level of Bcl-2 family members. Most importantly, the concomitant treatment simultaneously regulated the ephrin-B2 and VEGFR2 signaling, as well as modulated the MEK/ERK and PTEN/PI3K/AKT/mTOR signaling. Therefore, the combination treatment of TAB may be a promising therapeutic method in treating T-cell acute lymphoblastic leukemia. Copyright © 2017 John Wiley & Sons, Ltd.
Asunto(s)
Berberina/farmacología , Carbanilidas/farmacología , Efrina-B2/metabolismo , Hidroxilaminas/farmacología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Transducción de Señal/efectos de los fármacos , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Sinergismo Farmacológico , Humanos , Células Jurkat , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológicoRESUMEN
Leukemia is among the most aggressive and prevalent human malignant carcinoma. Chemotherapy is the preferred therapeutic strategy; however, recurrence of cancer and non-selective cytotoxicity are the major concerns. Unlike synthetic chemotherapeutic agents, mistletoe ribosome-inactivating protein (RIP) displays anti-tumor function in various types of cancers. However, its effect on leukemia cells is little explored. In this study, we assessed the impact of Viscum articulatum RIP (Articulatin-D) on the survival of acute T-cell leukemia cells and the involved molecular and cellular mechanisms. Cell proliferation assay showed that Articulatin-D suppressed the viability of leukemia cells selectively. We further confirmed that the elevation of mitochondrial membrane potential and exposure of phosphatidylserine are the early events of apoptosis induction in Articulatin-D-treated Jurkat cells. Subsequently, we found that Articulatin-D treatment induces apoptosis in Jurkat cells in a time- and concentration-dependent manner. In conclusion, we provided evidence that Articulatin-D efficiently activates caspase-8 involved in extrinsic pathway of apoptosis induction, which ultimately results in caspase-3-dependent DNA fragmentation of Jurkat cells. Further evaluation of Articulatin-D in cell culture and animal models may provide novel information on selective cytotoxicity to acute T-cell leukemia and its involvement in targeting tumor cell survival pathways.
Asunto(s)
Apoptosis/efectos de los fármacos , Caspasa 8/metabolismo , Proliferación Celular/efectos de los fármacos , Preparaciones de Plantas/farmacología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Proteínas Inactivadoras de Ribosomas Tipo 2/farmacología , Toxinas Biológicas/farmacología , Viscum/química , Fragmentación del ADN/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Humanos , Células Jurkat , Preparaciones de Plantas/química , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Proteínas Inactivadoras de Ribosomas Tipo 2/química , Toxinas Biológicas/químicaRESUMEN
Marsdenia tenacissimae extraction (MTE) as a traditional Chinese herb has long been used to treat some diseases such as tumors in China. However, the potential effectiveness of MTE in leukemia has not yet been fully understood, and the related molecular mechanism is still unknown. In the present study, we aimed to evaluate the effects of MTE on the proliferation and apoptosis of Jurkat cells (T-ALL lines) and lymphocytes from T-ALL (T-cell acute lymphoblastic leukemia) patients. Firstly, CCK8 assays and flow cytometry assays revealed that MTE dose-dependently reduced the proliferation of Jurkat cells by arresting cell cycle at S phase. Secondly, Annexin V-FITC/PI-stained flow cytometry and TUNEL staining assays showed that MTE promoted the apoptosis of Jurkat cells. Mechanistically, MTE enhanced PTEN (phosphatases and tensin homolog) level and inactivated PI3K/AKT/mTOR signaling pathway in Jurkat cells, which mediated the inhibition of cell proliferation by MTE and MTE-induced apoptosis. Finally, MTE significantly inhibited the proliferation and promoted the apoptosis of lymphocytes from T-ALL patients, compared with lymphocytes from healthy peoples. Taken together, these results reveal an unrecognized function of MTE in inhibiting the proliferation and inducing the apoptosis of T-ALL cells, and identify a pathway of PTEN/PI3K/AKT/mTOR for the effects of MTE on leukemia therapy.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Marsdenia , Fosfohidrolasa PTEN/metabolismo , Fosfatidilinositol 3-Quinasa/metabolismo , Extractos Vegetales/farmacología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Antineoplásicos Fitogénicos/aislamiento & purificación , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Células Jurkat , Marsdenia/química , Fitoterapia , Extractos Vegetales/aislamiento & purificación , Plantas Medicinales , Leucemia-Linfoma Linfoblástico de Células T Precursoras/enzimología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Puntos de Control de la Fase S del Ciclo Celular/efectos de los fármacos , Factores de Tiempo , Células Tumorales CultivadasRESUMEN
A new 6-hydroperoxyeunicellin diterpenoid, designated as cladieunicellin J (1), was isolated from an octocoral Cladiella sp., and its structure elucidated by spectroscopic methods. Compound 1 was found to exhibit cytotoxicity toward CCRF-CEM human T-cell acute lymphoblastic leukemia.
Asunto(s)
Antozoos/química , Diterpenos/aislamiento & purificación , Animales , Diterpenos/química , Diterpenos/farmacología , Humanos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologíaRESUMEN
We have previously demonstrated that CCR9 plays a pivotal role in drug resistance and invasion in human acute T-lymphocytic leukemia (T-ALL). In this study, we investigated whether the MOLT4 cells, which naturally express CCR9 at high levels, can be successfully killed by the specific ligand, CCL25 fused to Pseudomonas exotoxin 38 (PE38) toxin. Our results demonstrated that CCL25-PE38 was able to specifically kill MOLT4 cells via apoptosis induction, and suppress the growth of CCR9(+) tumors. This work shows that CCR9 high-expressing human T-ALL cells can be successfully killed by delivering PE38 toxin fused to the ligand CCL25.