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1.
Biol Pharm Bull ; 46(9): 1269-1276, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37661406

RESUMEN

Adult T-cell leukemia/lymphoma (ATL) is a hematopoietic malignancy with a poor prognosis that develops in approximately 5% of human T-cell leukemia virus type 1 (HTLV-1) carriers. Cyclin-dependent kinase 9 (CDK9), together with Cyclin T, forms a transcription elongation factor, positive transcription elongation factor b (P-TEFb). P-TEFb promotes transcriptional elongation by phosphorylating the second serine (Ser2) of the seven amino acid repeat sequence in the C-terminal domain of RNA polymerase II (RNAP II). CDK9 inhibitors suppress cell proliferation by inducing apoptosis in chronic lymphocytic leukemia and breast cancer but there are no reports on autophagy of CDK9 inhibitors. Here, we investigated the effect of LY2857785, a novel CDK9 selective inhibitor, on cell death in ATL-related cell lines in vitro, freshly isolated cells from ATL patients ex vivo, and on ATL tumor xenografts in NOD/SCID mice in vivo. LY2857785 significantly reduced cell viability and induced apoptosis, as shown by annexin V-positive cells, cleaved poly(ADP-ribose) polymerase (PARP), and cleaved caspase-3, and suppressed the levels of anti-apoptotic protein myeloid cell leukemia-1 (MCL-1). LY2857785 decreased RNAP II Ser2 phosphorylation and downstream c-Myc protein levels. Interestingly, LY2857785 also increased microtubule-associated proteins 1A/1B light chain 3B (LC3)-II binding to autophagosome membranes. Furthermore, LY2857785 decreased the viability of freshly isolated ATL cells and induced apoptosis. Finally, LY2857785 significantly decreased the growth of ATL tumor xenografts. These results suggest that LY2857785 induces cell death of ATL cells by MCL-1-dependent apoptosis and autophagy and has anti-tumor activity.


Asunto(s)
Neoplasias de la Mama , Leucemia-Linfoma de Células T del Adulto , Linfoma , Ratones , Adulto , Animales , Humanos , Femenino , Ratones Endogámicos NOD , Ratones SCID , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Factor B de Elongación Transcripcional Positiva , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Inhibidores de Proteínas Quinasas , Apoptosis , Autofagia , Quinasa 9 Dependiente de la Ciclina
2.
BMC Cancer ; 18(1): 791, 2018 Aug 06.
Artículo en Inglés | MEDLINE | ID: mdl-30081901

RESUMEN

BACKGROUND: Sirtuin 2 (SIRT2) is a member of the sirtuin family, nicotinamide adenine dinucleotide+-dependent deacylases, which participates in modulation of cell cycle control, neurodegeneration, and tumorigenesis. SIRT2 expression increases in acute myeloid leukemia blasts. Downregulation of SIRT2 using siRNA causes apoptosis of HeLa cells. Therefore, selective inhibitors of SIRT2 are candidate therapeutic agents for cancer. Adult T-cell leukemia/lymphoma (ATL) is a T-cell malignancy that has a poor prognosis and develops after long-term infection with human T-cell leukemia virus (HTLV)-1. Sirtuin 1 inhibition has been shown to induce apoptosis and autophagy in HTLV-1-infected cell lines, whereas the effects of SIRT2 inhibition alone have not been elucidated. METHODS: We assessed the efficacy of our small molecule selective SIRT2 inhibitors NCO-90/141 to induce leukemic cell death. Cell viability was examined using the cell proliferation reagent Cell Count Reagent SF. Apoptotic cells were detected by annexin V-FITC and terminal deoxynucleotidyl transferase dUTP nick end labeling assays by flow cytometry. Caspase activity was detected using an APOPCYTO Intracellular Caspase Activity Detection Kit. The presence of autophagic vacuoles was assessed using a Cyto-ID Autophagy Detection Kit. RESULTS: Our novel small molecule SIRT2-specific inhibitors NCO-90/141 inhibited cell growth of leukemic cell lines including HTLV-1-transformed T-cells. NCO-90/141 induced apoptosis via caspase activation and mitochondrial superoxide generation in leukemic cell lines. However, a caspase inhibitor did not prevent this caspase-associated cell death. Interestingly, NCO-90/141 increased the LC3-II level together with autophagosome accumulation, indicating autophagic cell death. Thus, NCO-90/141 simultaneously caused apoptosis and autophagy. CONCLUSIONS: These results suggest that NCO-90/141 are highly effective against leukemic cells in caspase-dependent or -independent manners via autophagy, and they may have a novel therapeutic potential for treatment of leukemias including ATL.


Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Inhibidores de Histona Desacetilasas/farmacología , Leucemia/tratamiento farmacológico , Sirtuina 2/antagonistas & inhibidores , Caspasas/metabolismo , Proliferación Celular/efectos de los fármacos , Células HL-60 , Humanos , Células Jurkat , Leucemia/enzimología , Leucemia/patología , Proteínas Asociadas a Microtúbulos/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/enzimología , Mitocondrias/patología , Transducción de Señal/efectos de los fármacos , Sirtuina 2/metabolismo , Superóxidos/metabolismo
3.
Molecules ; 19(12): 20295-313, 2014 Dec 04.
Artículo en Inglés | MEDLINE | ID: mdl-25486244

RESUMEN

Sirtuins are nicotinamide adenine dinucleotide+-dependent deacetylases of which there are seven isoforms (SIRT1-7). Sirtuin activity is linked to gene expression, lifespan extension, neurodegeneration, and age-related disorders. Numerous studies have suggested that sirtuins could be of great significance with regard to both antiaging and tumorigenesis, depending on its targets in specific signaling pathways or in specific cancers. Recent studies have identified small chemical compounds that modulate sirtuins, and these modulators have enabled a greater understanding of the biological function and molecular mechanisms of sirtuins. This review highlights the possibility of sirtuins, especially SIRT1 and SIRT2, for cancer therapy targets, and focuses on the therapeutic potential of sirtuin modulators both in cancer prevention and treatment.


Asunto(s)
Antineoplásicos/farmacología , Sirtuinas/antagonistas & inhibidores , Animales , Antineoplásicos/química , Muerte Celular/efectos de los fármacos , Muerte Celular/genética , Activadores de Enzimas/química , Activadores de Enzimas/farmacología , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , Humanos , Isoenzimas , Neoplasias/genética , Neoplasias/metabolismo , Sirtuinas/química , Sirtuinas/metabolismo
4.
Mod Rheumatol ; 23(1): 19-27, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-22374112

RESUMEN

OBJECTIVE: The ability of the ImmuKnow (Cylex) assay to predict the risk of infection in rheumatoid arthritis (RA) patients receiving synthetic or biological disease-modifying antirheumatic drugs (DMARDs) was examined. METHODS: The amount of adenosine triphosphate (ATP) produced by CD4+ cells in response to phytohemagglutinin was measured in whole blood from 117 RA patients without infection versus 17 RA patients with infection, and compared with results in 75 healthy controls. RESULTS: The mean ATP level was significantly lower in patients with infection compared to both healthy controls (P < 0.0005) and patients without infection (P = 0.040). Also, the mean ATP level in patients without infection was significantly lower than that in healthy controls (P = 0.012). There was no correlation between the ATP level and the Disease Activity Score in 28 joints. CONCLUSION: ImmuKnow assay results may be effective in identifying RA patients at increased risk of infection, but the results showed no correlation with RA activity. Larger studies are required to establish the clinical advantages of this assay in RA treatment.


Asunto(s)
Adenosina Trifosfato/sangre , Artritis Reumatoide/complicaciones , Linfocitos T CD4-Positivos/metabolismo , Infecciones/complicaciones , Adulto , Antirreumáticos/efectos adversos , Artritis Reumatoide/sangre , Artritis Reumatoide/tratamiento farmacológico , Linfocitos T CD4-Positivos/efectos de los fármacos , Femenino , Humanos , Inmunoensayo/métodos , Inmunosupresores/efectos adversos , Infecciones/etiología , Articulaciones/fisiopatología , Masculino , Persona de Mediana Edad , Fitohemaglutininas/farmacología , Valor Predictivo de las Pruebas , Riesgo , Índice de Severidad de la Enfermedad
5.
Eur J Pharmacol ; 961: 176180, 2023 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-37956732

RESUMEN

Adult T-cell leukemia/lymphoma (ATL) is an aggressive T cell leukemia/lymphoma caused by human T-cell lymphotropic virus type I (HTLV-1). Acadesine or 5-aminoimidazole-4-carboxamide riboside (AICAR) is an AMP-activated protein kinase (AMPK) activator that was recently shown to have tumor suppressive effects on B cell chronic lymphocytic leukemia, but not ATL. This study evaluated the cytotoxic effects of AICAR on ATL-related cell lines and its anti-tumor activity. Here, we demonstrated that AICAR induced cell death via apoptosis and the mitochondrial membrane depolarization of ATL-related cell lines (S1T, MT-1, and MT-2) but not non-HTLV-1-infected Jurkat cells. However, AICAR did not increase the phosphorylation levels of AMPKα. In addition, AICAR increased the expression of the death receptors (DR) DR4 and DR5, and necroptosis-related proteins including phosphorylated receptor-interacting protein family members and the mixed lineage kinase domain-like protein. Interestingly, HTLV-1 Tax, an HTLV-1-encoded oncogenic factor, did not affect AICAR-induced apoptosis. Furthermore, AICAR inhibited the growth of human ATL tumor xenografts in NOD/SCID/gamma mice in vivo. Together, these results suggest that AICAR induces AMPK-independent cell death in ATL-related cell lines and has anti-tumor activity, indicating that it might be a therapeutic agent for ATL.


Asunto(s)
Virus Linfotrópico T Tipo 1 Humano , Leucemia-Linfoma de Células T del Adulto , Ratones , Adulto , Animales , Humanos , Proteínas Quinasas Activadas por AMP/metabolismo , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Leucemia-Linfoma de Células T del Adulto/patología , Ratones Endogámicos NOD , Ratones SCID , Apoptosis
6.
Int J Cancer ; 131(9): 2044-55, 2012 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-22322739

RESUMEN

Adult T-cell leukemia-lymphoma (ATL) is an aggressive peripheral T-cell neoplasm that develops after long-term infection with human T-cell leukemia virus (HTLV-1). SIRT1, a nicotinamide adenine dinucleotide(+)-dependent histone/protein deacetylase, plays a crucial role in various physiological processes, such as aging, metabolism, neurogenesis and apoptosis, owing to its ability to deacetylate numerous substrates, such as histone and NF-κB, which is implicated as an exacerbation factor in ATL. Here, we assessed how SIRT1 is regulated in primary ATL cells and leukemic cell lines. SIRT1 expression in ATL patients was significantly higher than that in healthy controls, especially in the acute type. Sirtinol, a SIRT1 inhibitor, induced significant growth inhibition or apoptosis in cells from ATL patients and leukemic cell lines, especially HTLV-1-related cell lines. Sirtinol-induced apoptosis was mediated by activation of the caspase family and degradation of SIRT1 in the nucleus. Furthermore, SIRT1 knockdown by SIRT1-specific small interfering RNA caused apoptosis via activation of caspase-3 and PARP in MT-2 cells, HTLV-1-related cell line. These results suggest that SIRT1 is a crucial antiapoptotic molecule in ATL cells and that SIRT1 inhibitors may be useful therapeutic agents for leukemia, especially in patients with ATL.


Asunto(s)
Apoptosis , Benzamidas/farmacología , Leucemia-Linfoma de Células T del Adulto/metabolismo , Naftoles/farmacología , Sirtuina 1/metabolismo , Caspasa 3/metabolismo , Línea Celular Tumoral , Humanos , Leucemia-Linfoma de Células T del Adulto/genética , Poli(ADP-Ribosa) Polimerasas/metabolismo , Interferencia de ARN , ARN Interferente Pequeño , Sirtuina 1/antagonistas & inhibidores , Sirtuina 1/genética , Sirtuinas/antagonistas & inhibidores
7.
FEBS J ; 289(12): 3477-3488, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35029032

RESUMEN

Adult T-cell leukemia/lymphoma (ATL) develops after a long period of human T-cell leukemia virus (HTLV)-1 infection and is associated with host aging in addition to genetic abnormalities in HTLV-1 infected cells. SIRT1 is a histone deacetylase involved in cell cycle and apoptosis. We previously showed the high expression of SIRT1 protein in peripheral blood mononuclear cells from patients with ATL. There have been many reports that SIRT1 inhibitors show tumor-suppressive effects. On the other hand, SIRT1 activator SRT1720 induces the cell death of multiple myeloma and breast cancer cells. However, the effect of SRT1720 on ATL is unknown. This study aimed to evaluate the effect of SRT1720 on cell death in leukemic cell lines in vitro and freshly isolated ATL cells ex vivo and in an ATL in vivo mouse model. SRT1720 reduced cell viability in vitro and ex vivo. Additionally, SRT1720 increased the number of apoptotic cells, as shown by annexin V positive cells, cleaved poly (ADP-ribose) polymerase 1, cleaved caspase-3, and fragmented DNA. SRT1720 also induced mitochondrial outer membrane permeabilization with the generation of mitochondrial reactive oxygen species and autophagy. However, SIRT1 knockdown did not attenuate SRT1720-induced cell death in leukemic cell lines. Finally, SRT1720 treatment decreased the growth of human ATL tumor xenografts in immunodeficient mice. Our study shows that while SRT1720 does not target SIRT1, it induces cell death in ATL cells via apoptosis and autophagy and has antitumor activity.


Asunto(s)
Compuestos Heterocíclicos de 4 o más Anillos , Leucemia-Linfoma de Células T del Adulto , Animales , Apoptosis , Muerte Celular , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Humanos , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Leucemia-Linfoma de Células T del Adulto/genética , Leucemia-Linfoma de Células T del Adulto/metabolismo , Leucocitos Mononucleares/metabolismo , Ratones , Sirtuina 1/genética , Sirtuina 1/metabolismo
8.
J Med Virol ; 83(3): 501-9, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21264872

RESUMEN

Human T-cell lymphotropic virus type I (HTLV-1) causes adult T-cell leukemia/lymphoma and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The different patterns of clinical diseases are thought to be linked to immunogenetic host factors. A variety of autoimmune diseases, such as Sjögren's syndrome, have been reported in persons infected with HTLV-1, although the precise relationship between these disorders and HTLV-1 infection remains unknown. There is no report on the repertoire of HTLV-1-specific CD8+ T-cells in HAM/TSP patients or carriers with autoimmune diseases, both characterized by an abnormal immune state. In this study, to characterize HTLV-1-specific CD8+ T-cells in asymptomatic HTLV-1 carriers, HAM/TSP patients and carriers with autoimmune diseases, we examined the frequency and diversity of HTLV-1-specific CD8+ T-cells using HTLV-1 tetramers. HTLV-1 Env-specific CD8+ T-cells were significantly more frequent in HAM/TSP and carriers with autoimmune diseases compared with asymptomatic HTLV-1 carriers, while the frequency of HTLV-1 Tax-specific CD8+ T-cells was not significantly different among them. CD8+ cells binding to HTLV-1 Tax tetramers in carriers with autoimmune diseases were significantly reduced compared with HAM/TSP patients. This study demonstrates the importance of CD8+ T-cells recognizing HTLV-1 Env-tetramers in HAM/TSP patients and carriers with autoimmune diseases, thereby suggesting that the diversity, frequency and repertoire of HTLV-1 Env-specific CD8+ T-cell clones may be related to the hyperimmune response in HAM/TSP and carriers with autoimmune diseases, although different immunological mechanisms may mediate the hyperimmunity in these conditions.


Asunto(s)
Enfermedades Autoinmunes/inmunología , Epítopos , Virus Linfotrópico T Tipo 1 Humano/inmunología , Virus Linfotrópico T Tipo 1 Humano/metabolismo , Paraparesia Espástica Tropical/inmunología , Linfocitos T Citotóxicos , Adulto , Anciano , Anciano de 80 o más Años , Epítopos/inmunología , Epítopos/metabolismo , Productos del Gen tax/inmunología , Productos del Gen tax/metabolismo , Variación Genética , Antígenos HLA-A/química , Antígenos HLA-A/inmunología , Antígenos HLA-A/metabolismo , Prueba de Histocompatibilidad , Humanos , Persona de Mediana Edad , Unión Proteica , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/metabolismo , Proteínas del Envoltorio Viral/inmunología , Proteínas del Envoltorio Viral/metabolismo , Adulto Joven
9.
Mol Cell Biochem ; 339(1-2): 285-92, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-20148352

RESUMEN

Calorie restriction (CR) extends lifespans in a wide variety of species. CR induces an increase in the NAD(+)/NADH ratio in cells and results in activation of SIRT1, an NAD(+)-dependent protein deacetylase that is thought to be a metabolic master switch linked to the modulation of lifespans. CR also affects the expression of peroxisome proliferator-activated receptors (PPARs). The three subtypes, PPARalpha, PPARgamma, and PPARbeta/delta, are expressed in multiple organs. They regulate different physiological functions such as energy metabolism, insulin action and inflammation, and apparently act as important regulators of longevity and aging. SIRT1 has been reported to repress the PPARgamma by docking with its co-factors and to promote fat mobilization. However, the correlation between SIRT1 and other PPARs is not fully understood. CR initially induces a fasting-like response. In this study, we investigated how SIRT1 and PPARalpha correlate in the fasting-induced anti-aging pathways. A 24-h fasting in mice increased mRNA and protein expression of both SIRT1 and PPARalpha in the livers, where the NAD(+) levels increased with increasing nicotinamide phosphoribosyltransferase (NAMPT) activity in the NAD(+) salvage pathway. Treatment of Hepa1-6 cells in a low glucose medium conditions with NAD(+) or NADH showed that the mRNA expression of both SIRT1 and PPARalpha can be enhanced by addition of NAD(+), and decreased by increasing NADH levels. The cell experiments using SIRT1 antagonists and a PPARalpha agonist suggested that PPARalpha is a key molecule located upstream from SIRT1, and has a role in regulating SIRT1 gene expression in fasting-induced anti-aging pathways.


Asunto(s)
Ayuno , PPAR alfa/metabolismo , Sirtuina 1/metabolismo , Animales , Western Blotting , Citocinas/genética , Citocinas/metabolismo , Glucosa/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , NAD/metabolismo , Nicotinamida Fosforribosiltransferasa/genética , Nicotinamida Fosforribosiltransferasa/metabolismo , PPAR alfa/genética , PPAR gamma/genética , PPAR gamma/metabolismo , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sirtuina 1/genética
10.
FEBS J ; 287(18): 4005-4015, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32027454

RESUMEN

Adult T-cell leukemia/lymphoma (ATL) is an aggressive T-cell neoplasm with poor prognosis that develops after chronic infection with human T-cell leukemia virus type 1 (HTLV-1). Although AMP-activated protein kinase (AMPK) is a critical cellular energy sensor, it has recently become clear that AMPK can act as a tumor regulator. Here, we assessed the expression of AMPK in primary ATL cells and the effects of dorsomorphin, an AMPK inhibitor, on primary ATL cells and HTLV-1-infected T-cell lines. AMPK expression in acute and chronic ATL patients was significantly higher than in asymptomatic HTLV-1 carriers and healthy donors. Dorsomorphin induced apoptosis in peripheral blood mononuclear cells from ATL patients. Dorsomorphin also induced dose- and time-dependent apoptosis in HTLV-1-infected T-cell lines. Dorsomorphin increased the production of intracellular reactive oxygen species (ROS) and induced ataxia telangiectasia-mutated Ser1981 phosphorylation and p53 accumulation. These results indicated that dorsomorphin induces apoptosis via ROS-mediated DNA damage in HTLV-1-infected T-cell lines. Furthermore, dorsomorphin suppressed the growth of human ATL tumor xenografts in NOD/SCID mice. Together, these data suggest that AMPK could be a candidate therapeutic target for ATL and that dorsomorphin could be a therapeutic agent for ATL.


Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Apoptosis/efectos de los fármacos , Leucemia-Linfoma de Células T del Adulto/metabolismo , Pirazoles/farmacología , Pirimidinas/farmacología , Adulto , Animales , Línea Celular Tumoral , Femenino , Humanos , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Leucemia-Linfoma de Células T del Adulto/patología , Ratones , Ratones Endogámicos NOD , Ratones SCID , Inhibidores de Proteínas Quinasas/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto/métodos
11.
Life Sci ; 252: 117665, 2020 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-32305521

RESUMEN

AIMS: Thrombin formation is increased in patients with acute cerebral ischemic stroke, and augments coagulation and inflammation in the brain. Administration of antithrombin (AT) was previously reported to be protective against renal and myocardial ischemic injury. Thus, we hypothesized that treatment with AT would be neuroprotective against cerebral ischemic injury. This study evaluated the effects of AT treatment on ischemic inflammation and brain damage in mice subjected to middle cerebral artery occlusion (MCAO). MAIN METHODS: A mouse model of 4-hour MCAO was used to induce ischemic brain injury. Recombinant AT gamma was administered intravenously immediately after reperfusion at 4 h after MCAO. Infarct volume, neurological deficit, and regional cerebral blood flow (rCBF) were measured at 24 h after MCAO. To evaluate the effect of AT gamma on ischemic inflammation, we measured the number of Iba1-positive cells (marker of macrophage/microglial activation) and levels of proinflammatory cytokines. Further, we investigated the direct anti-inflammatory effects of rAT in the J774.1 cell line. KEY FINDINGS: Treatment with AT gamma (480 U/kg) reduced infarct volume and neurological deficit, and improved rCBF, in MCAO mice. Moreover, AT gamma treatment decreased the number of Iba1-positive cells and levels of proinflammatory cytokines. In vitro, treatment with thrombin significantly increased proinflammatory cytokine levels, which was significantly reduced by pretreatment with AT gamma. SIGNIFICANCE: Treatment with AT showed neuroprotective effects via anticoagulation actions, as well as direct anti-inflammatory effects on macrophage/microglial activation. These data suggest that AT may be a useful new therapeutic option for cerebral ischemia.


Asunto(s)
Antitrombinas/farmacología , Isquemia Encefálica/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Accidente Cerebrovascular/tratamiento farmacológico , Animales , Antitrombinas/administración & dosificación , Isquemia Encefálica/patología , Línea Celular , Citocinas/metabolismo , Modelos Animales de Enfermedad , Infarto de la Arteria Cerebral Media , Inflamación/tratamiento farmacológico , Inflamación/patología , Activación de Macrófagos/efectos de los fármacos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Microglía/efectos de los fármacos , Microglía/metabolismo , Fármacos Neuroprotectores/administración & dosificación , Proteínas Recombinantes , Accidente Cerebrovascular/patología
12.
Eur J Pharmacol ; 865: 172738, 2019 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-31614144

RESUMEN

Adult T-cell leukemia/lymphoma (ATL) is a malignancy of mature T lymphocytes induced by human T-cell leukemia virus-1 and has a poor outcome. New molecular targets for the prevention and treatment of ATL are needed urgently. We previously reported high expression of Sirtuin 1, a nicotinamide adenine dinucleotide (NAD+)-dependent histone/protein deacetylase, in primary acute-type ATL cells. NAD+ biosynthesis via nicotinamide phosphoribosyltransferase (NAMPT) modulates Sirtuin 1 activity. Here, we examined the expression and effects of inhibiting NAMPT, a rate-limiting enzyme in NAD+ biosynthesis, in ATL cells. We found that peripheral blood mononuclear cells from patients with acute-type ATL expressed significantly higher levels of NAMPT protein than cells from healthy subjects. FK866, a NAMPT inhibitor, induced apoptosis of freshly isolated ATL cells ex vivo and HTLV-1-infected T-cell lines in vitro, which was accompanied by activation of caspases, DNA fragmentation, and disruption of mitochondrial transmembrane potential. However, a pan-caspase inhibitor failed to prevent this FK866-induced cell death, while FK866 increased the caspase-independent cell death mediator endonuclease G. Intriguingly, FK866 also activated autophagy, as demonstrated by increases in protein levels of autophagosome marker LC3-II. Thus, FK866 simultaneously activated apoptosis and autophagy. Finally, FK866 treatment markedly decreased the growth of human ATL tumor xenografts in immunodeficient mice. We showed that NAMPT is highly expressed in primary ATL cells ex vivo, and that FK866 induces autophagy and caspase-dependent and -independent cell death pathways in vitro and has an anti-tumor activity in vivo. These results suggest a novel therapeutic strategy for patients with this fatal disease.


Asunto(s)
Antineoplásicos/farmacología , Citocinas/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Leucemia-Linfoma de Células T del Adulto/patología , Nicotinamida Fosforribosiltransferasa/antagonistas & inhibidores , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Caspasa 3/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Humanos
13.
Animal Model Exp Med ; 2(1): 64-67, 2019 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31016289

RESUMEN

Adult T-cell leukemia (ATL) is a mature T-cell malignancy caused by human T-cell leukemia virus type I infection, and 10%-25% of patients show central nervous system (CNS) involvement. CNS involvement significantly reduces survival and there are no effective treatments for CNS involvement. Therefore, an appropriate animal model is required to evaluate the inhibitory effects of novel drugs on the progression of ATL with CNS involvement. Here, we established a mouse model of ATL with CNS involvement using NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ mice inoculated with ATL cells intramuscularly in the postauricular region, and these mice showed paraparesis. Of the 10 mice inoculated with ATL cells intramuscularly (I.M.) at 5 weeks of age, 8 (80%) showed paraparesis, whereas none of the 10 mice inoculated with ATL cells subcutaneously (S.C.) showed paraparesis. In the I.M. group, PCR detected HTLV-1-specific genes in the thoracic and lumbar vertebrae; however, in the S.C. group, the vertebrae were negative for HTLV-1 genes. Histological analysis revealed a particularly high incidence of tumors, characterized by accumulation of the injected cells, in the thoracic vertebrae of mice in the I.M. group. Tumor cell infiltration was relatively high in the bone marrow. Spinal cord compression caused by invasion of the tumor mass outside the pia mater was observed in the thoracic vertebrae of the spinal cord. In conclusion, we have reported a mouse model of tumor growth with paraparesis that may be used to assess novel therapeutic agents for ATL with CNS involvement.

14.
Thromb Haemost ; 100(6): 1014-20, 2008 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19132224

RESUMEN

Plasminogen activator inhibitor-1 (PAI-1), a member of the serpin gene family, is the primary inhibitor of urokinase-type and tissue-type PAs. PAI-1 plays an important role in the process of peripheral tissue remodeling and fibrinolysis through the regulation of PA activity. This serpin is also produced in brain tissues and may regulate the neural protease sequence in the central nervous system (CNS), as it does in peripheral tissues. In fact, PAI-1 mRNA is up-regulated in mouse brain after stroke. The serpin activity of PAI-1 helps to prevent tissue-type PA-induced neuron death. However, we have previously found that PAI-1 has a novel biological function in the CNS: the contribution to survival of neurites on neurons. In neuronally differentiated rat pheochromocytoma (PC-12) cells, a deficiency of PAI-1 in vitro caused a significant reduction in Bcl-2 and Bcl-X(L) mRNAs and an increase in Bcl-X(S) and Bax mRNAs. The change in the balance between mRNA expressions of the anti- and pro-apoptotic Bcl-2 family proteins promoted the apoptotic sequence: caspase-3 activation, cytochrome c release from mitochondria and DNA fragmentation. Our results indicate that PAI-1 has an anti-apoptotic role in neurons. PAI-1 prevented the disintegration of the formed neuronal networks by maintaining or promoting neuroprotective signaling through the MAPK/ERK pathway, suggesting that the neuroprotective effect of PAI-1 is independent of its action as a protease inhibitor. This review discusses the neuroprotective effects of PAI-1 in vitro, together with the relevant data from other laboratories. Special emphasis is placed on its action on PC-12 cells.


Asunto(s)
Apoptosis , Sistema Nervioso Central/metabolismo , Factores de Crecimiento Nervioso/metabolismo , Neuronas/metabolismo , Inhibidor 1 de Activador Plasminogénico/metabolismo , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Animales , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Astrocitos/metabolismo , Astrocitos/patología , Supervivencia Celular , Sistema Nervioso Central/enzimología , Sistema Nervioso Central/patología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Humanos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Factor de Crecimiento Nervioso/metabolismo , Neuritas/metabolismo , Neuritas/patología , Neuronas/enzimología , Neuronas/patología , Células PC12 , Ratas , Receptor trkA/metabolismo , Transducción de Señal
15.
Oncol Lett ; 16(1): 1305-1311, 2018 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-30061950

RESUMEN

Despite the efficacy of combination chemotherapy with arsenic trioxide (ATO), interferon α (IFN) and zidovudine (AZT) for adult T cell leukemia/lymphoma (ATL), the precise mechanism underlying this combination treatment effect is unknown. In the present study, ATO/IFN/AZT was examined in an ATL leukemic cell line (S1T, non-Tax expressing), a human T-lymphotropic virus 1 (HTLV-1)-infected cell line (MT2, Tax-expressing) and primary ATL cells from patients with acute and chronic ATL. IFN/AZT marginally inhibited MT2 cell proliferation, but substantially inhibited S1T cell proliferation. IFN/AZT increased the cleavage of numerous caspases and PARP in S1T cells, and regulated the signal transducer and activator of transcription 1 and nuclear factor-κB signaling pathway. These effects represent the potential anti-ATL mechanisms of INF/AZT in vitro. In addition, the combination of ATO and IFN/AZT demonstrated synergistic effects on S1T cells. Therefore, the Tax-independent mechanism underlying the anti-ATL effect of ATO must be further elucidated.

16.
Oncotarget ; 9(45): 27645-27655, 2018 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-29963226

RESUMEN

Adult T cell leukemia/lymphoma (ATL) is an aggressive malignant T cell disease caused by human T cell leukemia virus-I (HTLV-1). Treatment outcomes for aggressive subtypes of ATL remain poor, with little improvement in overall survival since HTLV-1 was discovered. Therefore, new therapeutic strategies for ATL are required. STF-62247 induces autophagy and selectively kills renal cell carcinoma without apoptotic cell death. Here, we demonstrate that STF-62247 reduced cell viability and resulted in autophagosome accumulation and autophagy in leukemic cell lines (S1T, MT-2, and Jurkat). Interestingly, STF-62247 induced apoptosis in HTLV-1-infected cell lines (S1T and MT-2), as indicated by DNA fragmentation and caspase activation, but not in non-HTLV-1-infected Jurkat cells; a caspase inhibitor did not prevent this caspase-associated cell death. STF-62247 also increased nuclear endonuclease G levels. Furthermore, STF-62247 reduced cell viability and increased the number of apoptotic cells in peripheral blood mononuclear cells collected from patients with acute ATL, which has a poor prognosis. Therefore, STF-62247 may have novel therapeutic potential for ATL. This is the first evidence to demonstrate the cell growth-inhibitory effect of an autophagy inducer by caspase-dependent apoptosis and caspase-independent cell death via autophagy and endonuclease G in leukemic cells.

17.
FEBS Open Bio ; 6(5): 442-60, 2016 05.
Artículo en Inglés | MEDLINE | ID: mdl-27419050

RESUMEN

Adult T-cell leukemia/lymphoma (ATL), an aggressive T-cell malignancy that develops after long-term infection with human T-cell leukemia virus (HTLV-1), requires new treatments. Drug repositioning, reuse of a drug previously approved for the treatment of another condition to treat ATL, offers the possibility of reduced time and risk. Among clinically available angiotensin II receptor blockers, telmisartan is well known for its unique ability to activate peroxisome proliferator-activated receptor-γ, which plays various roles in lipid metabolism, cellular differentiation, and apoptosis. Here, telmisartan reduced cell viability and enhanced apoptotic cells via caspase activation in ex vivo peripheral blood monocytes from asymptomatic HTLV-1 carriers (ACs) or via caspase-independent cell death in acute-type ATL, which has a poor prognosis. Telmisartan also induced significant growth inhibition and apoptosis in leukemia cell lines via caspase activation, whereas other angiotensin II receptor blockers did not induce cell death. Interestingly, telmisartan increased the LC3-II-enriched protein fraction, indicating autophagosome accumulation and autophagy. Thus, telmisartan simultaneously caused caspase activation and autophagy. A hypertension medication with antiproliferation effects on primary and leukemia cells is intriguing. Patients with an early diagnosis of ATL are generally monitored until the disease progresses; thus, suppression of progression from AC and indolent ATL to acute ATL is important. Our results suggest that telmisartan is highly effective against primary cells and leukemia cell lines in caspase-dependent and -independent manners, and its clinical use may suppress acute transformation and improve prognosis of patients with this mortal disease. This is the first report demonstrating a cell growth-inhibitory effect of telmisartan in fresh peripheral blood mononuclear cells from leukemia patients.

18.
Leuk Lymphoma ; 57(3): 685-91, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-26077361

RESUMEN

Human T-lymphotropic virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia/lymphoma (ATL). Miscellaneous host immune surveillance systems control T-cell growth/leukemogenesis during HTLV-1 infection. We characterized CD70 and CD27 expression on lymphocytes of HTLV-1 carriers and patients with ATL (study approved by the local Medical Ethical Committee). High CD70 expression was observed on CD4 + CD25+ T cells from patients with acute-type ATL, while patients with smoldering- or chronic-type ATL and HTLV-1 carriers exhibited lower expression. Furthermore, significantly higher CD27 expression was observed on HTLV-1-specific CTLs. We found an association between CD70 expression on CD4 + T cells and HTLV-1 infection; increased CD70 expression was observed after exposure to Tax. Moreover, addition of anti-CD70 antibodies enhanced the CD107a surface mobilization of HTLV-1 Tax-specific CTLs following Tax-peptide stimulation in the PBMCs of carriers. These data demonstrate the important role of the CD70/CD27 axis in immune responses in HTLV-1 carriers and ATL patients.


Asunto(s)
Ligando CD27/metabolismo , Infecciones por HTLV-I/complicaciones , Infecciones por HTLV-I/virología , Virus Linfotrópico T Tipo 1 Humano , Leucemia-Linfoma de Células T del Adulto/etiología , Leucemia-Linfoma de Células T del Adulto/metabolismo , Linfocitos T/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD/genética , Antígenos CD/metabolismo , Ligando CD27/genética , Línea Celular Tumoral , Femenino , Expresión Génica , Productos del Gen tax/genética , Productos del Gen tax/metabolismo , Infecciones por HTLV-I/inmunología , Virus Linfotrópico T Tipo 1 Humano/inmunología , Humanos , Inmunofenotipificación , Masculino , Persona de Mediana Edad , Fenotipo , Linfocitos T/patología , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/metabolismo
19.
Sci Rep ; 5: 11345, 2015 Jun 19.
Artículo en Inglés | MEDLINE | ID: mdl-26091232

RESUMEN

Adult T-cell leukaemia/lymphoma (ATL) is an aggressive T-cell malignancy that develops after long-term infection with human T-cell leukaemia virus (HTLV)-1. The identification of new molecular targets for ATL prevention and treatment is desired. SIRT1, a nicotinamide adenine dinucleotide(+) -dependent histone/protein deacetylase, plays crucial roles in various physiological processes, including aging and apoptosis. We previously reported that ATL patients had significantly higher SIRT1 protein levels than healthy controls. Here, we demonstrate that two novel small-molecule SIRT1 inhibitors, NCO-01/04, reduced cell viability and enhanced apoptotic cells in peripheral blood monocyte cells of patients with acute ATL, which has a poor prognosis. NCO-01/04 also reduced the cell viability with DNA fragmentation, Annexin V-positive cells, and caspase activation. However, a caspase inhibitor did not inhibit this caspase-dependent cell death. NCO-01/04 enhanced the endonuclease G level in the nucleus with loss of the mitochondrial transmembrane potential, which can promote caspase-independent death. Interestingly, NCO-01/04 increased the LC3-II-enriched protein fraction, indicating autophagosome accumulation as well as autophagy. Thus, NCO-01/04 simultaneously caused caspase activation and autophagy. These results suggest that NCO-01/04 is highly effective against ATL cells in caspase-dependent or -independent manners with autophagy, and that its clinical application might improve the prognosis of patients with this fatal disease.


Asunto(s)
Antineoplásicos/farmacología , Muerte Celular/efectos de los fármacos , Inhibidores de Histona Desacetilasas/farmacología , Leucemia-Linfoma de Células T del Adulto/metabolismo , Sirtuina 1/antagonistas & inhibidores , Acetilación/efectos de los fármacos , Anexina A5/metabolismo , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Caspasas/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Histonas/metabolismo , Humanos , Leucocitos Mononucleares/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Sirtuina 1/metabolismo , Células Tumorales Cultivadas
20.
J Chem Neuroanat ; 25(2): 73-82, 2003 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-12663056

RESUMEN

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is considered to be one of the most toxic environmental contaminants, named dioxin. Exposure to TCDD induces a plethora of intoxication symptoms, including anorexia and hypothermia, in several mammals and human. Enkephalin, an endogenous pentapeptide, is an important neuroregulator of autonomic functions, such as food intake and body temperature. In this study, we investigated the effects of TCDD gastric administration on methionine-enkephalin (MEK) immunoreactivity in the brain of the Long-Evans rat, the species strain considered to be the most TCDD-susceptible, using immunohistochemical staining. A single dose of TCDD (dissolved in olive oil, 50 microg/kg) or olive oil alone was administrated to the rats by gavage. Compared with the vehicle-treated rat, a marked increase in the density of MEK immunoreactive cell bodies, fibers and terminals was found 2 weeks after TCDD treatment in the forebrain of the TCDD-treated rat, i.e. the central amygdaloid nucleus, field CA3 of the hippocampus, paraventricular hypothalamic nucleus, medial preoptic nucleus, interstitial nucleus of the posterior limb of the anterior commissure, lateral globus pallidus, ventral pallidum and lateral division of the bed nucleus of the stria terminalis. These results demonstrated for the first time a site-specific increased enkephalinergic activity in certain brain regions of the Long-Evans rat. It is suggested that the increased MEK immunoreactivity may act as a compensatory adaptation for the pathophysiological alterations caused by TCDD exposure.


Asunto(s)
Encefalina Metionina/biosíntesis , Dibenzodioxinas Policloradas/farmacología , Prosencéfalo/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos , Animales , Encefalina Metionina/análisis , Inmunohistoquímica , Masculino , Prosencéfalo/química , Prosencéfalo/metabolismo , Ratas , Ratas Long-Evans , Regulación hacia Arriba/fisiología
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