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1.
J Evol Biol ; 30(7): 1303-1312, 2017 07.
Artículo en Inglés | MEDLINE | ID: mdl-28425158

RESUMEN

Theory predicts trade-offs between pre- and post-copulatory sexually selected traits. This relationship may be mediated by the degree to which males are able to monopolize access to females, as this will place an upper limit on the strength of post-copulatory selection. Furthermore, traits that aid in mate monopolization may be costly to maintain and may limit investment in post-copulatory traits, such as sperm performance. Australian painted dragons are polymorphic for the presence or absence of a yellow gular patch ('bibs'), which may aid them to monopolize access to females. Previous work has shown that there are physiological costs of carrying this bib (greater loss of body condition in the wild). Here, we show that male painted dragons use this bright yellow bib as both an inter- and intrasexual signal, and we assess whether this signal is traded off against sperm performance within the same individuals. We found no relationship between aspects of bib colour and sperm swimming velocity or percentage of motile sperm and suggest that the bib polymorphism may be maintained by complex interactions between physiological or life-history traits including other sperm or ejaculate traits and environmental influences.


Asunto(s)
Lagartos , Conducta Sexual Animal , Espermatozoides/fisiología , Animales , Australia , Color , Femenino , Masculino , Pigmentación , Conducta Sexual
2.
J Evol Biol ; 29(5): 952-64, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-26809830

RESUMEN

Natural selection and post-copulatory sexual selection, including sexual conflict, contribute to genital diversification. Fundamental first steps in understanding how these processes shape the evolution of specific genital traits are to determine their function experimentally and to understand the interactions between female and male genitalia during copulation. Our experimental manipulations of male and female genitalia in red-sided garter snakes (Thamnophis sirtalis parietalis) reveal that copulation duration and copulatory plug deposition, as well as total and oviductal/vaginal sperm counts, are influenced by the interaction between male and female genital traits and female behaviour during copulation. By mating females with anesthetized cloacae to males with spine-ablated hemipenes using a fully factorial design, we identified significant female-male copulatory trait interactions and found that females prevent sperm from entering their oviducts by contracting their vaginal pouch. Furthermore, these muscular contractions limit copulatory plug size, whereas the basal spine of the male hemipene aids in sperm and plug transfer. Our results are consistent with a role of sexual conflict in mating interactions and highlight the evolutionary importance of female resistance to reproductive outcomes.


Asunto(s)
Copulación , Conducta Sexual Animal , Serpientes , Espermatozoides , Animales , Femenino , Genitales Femeninos , Genitales Masculinos , Masculino , Reproducción
3.
Nat Med ; 2(5): 574-7, 1996 May.
Artículo en Inglés | MEDLINE | ID: mdl-8616718

RESUMEN

Cytotoxic drugs used in chemotherapy of leukemias and solid tumors cause apoptosis in target cells. In lymphoid cells the CD95 (APO-1/Fas)/CD95 ligand (CD95-L) system is a key regulator of apoptosis. Here we describe that doxorbicin induces apoptosis via the CD95/CD95-L system in human leukemia T-cell lines. Doxorubicin-induced apoptosis was completely blocked by inhibition of gene expression and protein synthesis. Also, doxorbicin strongly stimulates CD95-L messenger RNA expression in vitro at concentrations relevant for therapy in vivo. CEM and jurkat cells resistant to CD95-mediated apoptosis were also resistant to doxorbicin-induced apoptosis . Furthermore, doxorbicin-induced apoptosis was inhibited by blocking F(ab')2 anti-APO-1 (anti-CD95) antibody fragments. Expression of CD95-L mRNA and protein in vitro was also stimulated by other cytotoxic drugs such as methotrexate. The finding that apoptosis caused by anticancer drugs may be mediated via the CD95 system provides a new molecular insight into resistance and sensitivity toward chemotherapy in malignancies.


Asunto(s)
Antibióticos Antineoplásicos/farmacología , Apoptosis , Doxorrubicina/farmacología , Leucemia-Linfoma de Células T del Adulto , Glicoproteínas de Membrana/metabolismo , Receptor fas/metabolismo , Antimetabolitos Antineoplásicos/farmacología , Cicloheximida/farmacología , Ciclosporina/farmacología , Relación Dosis-Respuesta a Droga , Proteína Ligando Fas , Humanos , Metotrexato/farmacología , Inhibidores de la Síntesis de la Proteína/farmacología , Células Tumorales Cultivadas
4.
Nuklearmedizin ; 49 Suppl 1: S31-6, 2010.
Artículo en Alemán | MEDLINE | ID: mdl-21152691

RESUMEN

Despite good achievements in prevention and control, cancer is still a leading cause of death worldwide. The development of resistances against conventional treatment modalities is one of the main causes of failure in the treatment of cancer. Radio- and chemotherapies fail frequently due to intrinsic or acquired resistances in apoptotic signalling pathways or alterations in DNA-repair processes. Targeted radiotherapies employing α-particle-emitting radionuclides and Auger-emitting electrons are a promising approach in cancer treatment to break radio- and chemoresistance by overcoming DNA-repair mechanisms and reversing deficient activation of apoptotic pathways in cancer cells.


Asunto(s)
Neoplasias/fisiopatología , Neoplasias/radioterapia , Tolerancia a Radiación , Radioterapia Conformacional/tendencias , Animales , Humanos , Insuficiencia del Tratamiento
5.
Rev Sci Instrum ; 91(10): 103102, 2020 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-33138582

RESUMEN

We present a novel locking scheme for active length-stabilization and frequency detuning of a cavity optomechanical device based on the optical spring effect. The error signal is generated by utilizing the position measurement of a thermally driven intra-cavity nanomechanical device and employing its detuning-dependent frequency shift caused by the dispersive coupling to the cavity field. The scheme neither requires external modulation of the laser or the cavity nor does it demand for additional error signal readout, rendering its technical implementation rather simple for a large variety of existing optomechanical devices. Specifically, for large-linewidth microcavities or in situations where other locking schemes appear unfavorable conceptually or are hard to realize technically, the optical spring lock represents a potential alternative for stabilizing the cavity length. We explain the functional principle of the lock and characterize its performance in terms of bandwidth and gain profile.

7.
Can J Cardiovasc Nurs ; 19(1): 20-5, 2009.
Artículo en Inglés | MEDLINE | ID: mdl-19226887

RESUMEN

Inactivity and unhealthy eating are precursors to the development of coronary artery disease. In Atlantic Canada, there is a widely recognized escalation of obesity and Type 2 diabetes in children. Our multidisciplinary group developed a three-year program targeting children in grades 4, 5 and 6 in an effort to alter this debilitating life course. This pilot program comprises education, physical activity, evaluation and research. Working in teams, students' physical activity levels and pedometer readings are tracked as they virtually walk across Canada. Monthly motivation assemblies and feature activities are integrated into the program. Evaluation of the education component is provided by pre- and post-tests. Evaluation of the physical activity component is composed of the activity logbooks. Parent and teacher surveys are administered once a year.


Asunto(s)
Trastornos de la Nutrición del Niño/prevención & control , Diabetes Mellitus Tipo 2/prevención & control , Promoción de la Salud/organización & administración , Obesidad/prevención & control , Prevención Primaria/organización & administración , Servicios de Salud Escolar/organización & administración , Niño , Trastornos de la Nutrición del Niño/complicaciones , Trastornos de la Nutrición del Niño/epidemiología , Enfermedad Coronaria/epidemiología , Enfermedad Coronaria/etiología , Enfermedad Coronaria/prevención & control , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/epidemiología , Ejercicio Físico , Conducta Alimentaria/psicología , Humanos , Estilo de Vida , Modelos Logísticos , Nueva Escocia/epidemiología , Obesidad/complicaciones , Obesidad/epidemiología , Padres/educación , Padres/psicología , Proyectos Piloto , Desarrollo de Programa , Evaluación de Programas y Proyectos de Salud , Medición de Riesgo , Conducta de Reducción del Riesgo
8.
Pediatr Obes ; 14(1)2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30257076

RESUMEN

BACKGROUND: Children with obesity are more likely to suffer gastroesophageal reflux disease, requiring acid-suppression therapy with proton pump inhibitors (PPIs) and no guidelines regarding dosing. OBJECTIVE: To prospectively evaluate lean-body-weight-based (LBW) dosing of the PPI pantoprazole for children with and without obesity. METHODS: Methods: Sixty-two children (6-17 years) received a one-time oral dose of liquid pantoprazole (1.2 mg kg-1 LBW). Plasma pantoprazole concentrations were measured at 10 time points over 8 h and pharmacokinetic (PK) profiles generated using non-compartmental techniques, in order to compare PK parameters of interest between children with and without obesity, while accounting for CYP2C19 genotype. RESULTS: Adjusted for milligram-per-kilogram total body weight (TBW) pantoprazole received, apparent drug clearance (CL/F) was reduced 50% in children with vs. without obesity (p=0.03). LBW-based dosing compensated for this reduction in CL/F (p = 0.15). CONCLUSION: To achieve comparable systemic PPI exposures for children with and without obesity, we recommend using LBW, rather than TBW-based dosing for pantoprazole.


Asunto(s)
Peso Corporal/efectos de los fármacos , Reflujo Gastroesofágico/tratamiento farmacológico , Pantoprazol/administración & dosificación , Obesidad Infantil/complicaciones , Inhibidores de la Bomba de Protones/administración & dosificación , Adolescente , Niño , Citocromo P-450 CYP2C19/genética , Cálculo de Dosificación de Drogas , Femenino , Estudios de Seguimiento , Reflujo Gastroesofágico/etiología , Genotipo , Humanos , Masculino , Pantoprazol/farmacocinética , Obesidad Infantil/tratamiento farmacológico , Estudios Prospectivos , Inhibidores de la Bomba de Protones/farmacocinética
9.
Neurogastroenterol Motil ; 19(5): 376-82, 2007 May.
Artículo en Inglés | MEDLINE | ID: mdl-17509019

RESUMEN

The aim of this study was to investigate the correlation of gastric myoelectrical and autonomic activities in healthy children. Simultaneous recordings of electrogastrography (EGG) and electrocardiogram (ECG) were performed in healthy children before and after a solid meal and water loading respectively. The autonomic activity was assessed by spectral analysis of the heart rate variability (HRV). The solid meal resulted in an increase in EGG-dominant frequency (2.92 cpm vs 3.16 cpm, P < 0.05), dominant power (46.9 dB vs 53.7 dB, P < 0.05) and percentage normal slow waves (81.9%vs 89.0%, P < 0.05), while only dominant power increased following water loading. Power in the low-frequency band of HRV (LF) was significantly increased and power in the high-frequency band of HRV (HF) significantly decreased following the solid meal. Postprandial LF was positively and HF negatively correlated with the postprandial increase in EGG-dominant power. Water loading was not associated with any significant changes in HRV parameters. These results suggest that both vagal and sympathetic pathways are involved in modulation of gastric myoelectrical activity.


Asunto(s)
Sistema Nervioso Autónomo/fisiología , Ingestión de Líquidos , Ingestión de Alimentos , Estómago , Adolescente , Niño , Electrocardiografía , Electromiografía , Femenino , Frecuencia Cardíaca/fisiología , Humanos , Masculino , Estómago/inervación , Estómago/fisiología
10.
Neurogastroenterol Motil ; 29(11)2017 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-28656703

RESUMEN

BACKGROUND: There have been no empirical validations of the Rome III or Rome IV criteria in children. The aim of the current study was to examine whether symptoms naturally occur in a pattern consistent with Rome III and/or Rome IV pediatric criteria for functional dyspepsia (FD) and irritable bowel syndrome (IBS). METHODS: We conducted a retrospective cohort study of 250 children, ages 8-17 years, presenting to an abdominal pain clinic with pain of at least 8 weeks duration. We evaluated patterns of gastrointestinal (GI) and non-gastrointestinal (non-GI) symptoms which had been collected in a standardized fashion as part of routine clinical care. Confirmatory factor analyses were used to compare pre-existing models of symptoms clusters, namely Rome III and Rome IV criteria for IBS and FD in children and adolescents. Factor intercorrelations also were examined to determine whether IBS symptoms and non-GI somatic complaints correlate uniquely with FD symptom clusters. KEY RESULTS: Both models demonstrated good fit with observed data [3-factor: χ2 (101, n=250)110.75, P<.05, TLI=.99, CFI=.99; 4-factor: χ2 (98, n=250)117.54, P<.05, TLI=.96, CFI=.97]. Fit indices and intercorrelations favored the more parsimonious 3-factor solution (3-factor: AIC=4654.91, BIC=4778.17; 4-factor: AIC=4757.16, BIC=4890.97) consistent with pediatric Rome III criteria that conceptualizes FD as a single diagnostic category. FD demonstrated significant overlap with IBS (.42), while non-GI-specific symptoms correlated significantly with FD (.64), but not IBS (.14) symptoms. CONCLUSIONS & INFERENCES: GI symptoms in children presenting for initial evaluation of chronic functional abdominal pain occur in a pattern consistent with Rome III and IV pediatric criteria. Rome III offers a more parsimonious model. The presence of FD symptoms is strongly, and uniquely, associated with non-GI symptoms.


Asunto(s)
Dolor Abdominal/diagnóstico , Dispepsia/diagnóstico , Síndrome del Colon Irritable/diagnóstico , Dolor Abdominal/complicaciones , Adolescente , Niño , Dispepsia/complicaciones , Femenino , Enfermedades Gastrointestinales/complicaciones , Enfermedades Gastrointestinales/diagnóstico , Humanos , Síndrome del Colon Irritable/complicaciones , Masculino , Estudios Retrospectivos , Índice de Severidad de la Enfermedad
12.
Cancer Res ; 57(17): 3823-9, 1997 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-9288794

RESUMEN

Anticancer agents have been shown to trigger apoptosis in chemosensitive tumors such as neuroblastomas. We previously identified activation of the CD95 system as one of the key mechanisms for doxorubicin-induced apoptosis in leukemic T cells. Here, we report that therapeutic concentrations of doxorubicin, cisplatinum, and VP-16 led to induction of CD95 receptor and CD95 ligand (CD95-L) that mediated cell death in chemosensitive neuroblastoma cells. Using F(ab')2 anti-CD95 antibody fragments to interfere with CD95-L-receptor interaction markedly reduced apoptosis induced by those drugs in vitro. Cyclosporin A inhibited induction of CD95 mRNA and CD95-L mRNA and blocked drug-mediated apoptosis. Drug-induced apoptosis involved activation of caspases (interleukin 1beta-converting enzyme/Ced-3-like proteases) and processing of the prototype caspase substrate PARP and was completely blocked by benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone, a peptide inhibitor of caspases. In addition, neuroblastoma cells that were resistant to CD95-triggered apoptosis also displayed cross-resistance to chemotherapeutic agents. These data provide new clues for understanding the molecular requirements for drug-induced apoptosis in chemosensitive neuroblastoma cells by demonstrating that cell death was mediated via the CD95-L-receptor system and may open new avenues for targeting drug resistance of neuroblastoma.


Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Glicoproteínas de Membrana/efectos de los fármacos , Neuroblastoma/patología , Receptor fas/efectos de los fármacos , Apoptosis/genética , Cisplatino/farmacología , Ciclosporina/farmacología , Cisteína Endopeptidasas/metabolismo , Fragmentación del ADN/efectos de los fármacos , Doxorrubicina/farmacología , Resistencia a Antineoplásicos , Activación Enzimática , Etopósido/farmacología , Proteína Ligando Fas , Humanos , Fragmentos de Inmunoglobulinas/farmacología , Inmunosupresores/farmacología , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Neuroblastoma/genética , Neuroblastoma/metabolismo , ARN Mensajero/metabolismo , Células Tumorales Cultivadas/efectos de los fármacos , Regulación hacia Arriba , Receptor fas/genética , Receptor fas/metabolismo
13.
Cancer Res ; 57(21): 4956-64, 1997 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-9354463

RESUMEN

Betulinic acid (BA), a melanoma-specific cytotoxic agent, induced apoptosis in neuroectodermal tumors, such as neuroblastoma, medulloblastoma, and Ewing's sarcoma, representing the most common solid tumors of childhood. BA triggered an apoptosis pathway different from the one previously identified for standard chemotherapeutic drugs. BA-induced apoptosis was independent of CD95-ligand/receptor interaction and accumulation of wild-type p53 protein, but it critically depended on activation of caspases (interleukin 1beta-converting enzyme/Ced-3-like proteases). FLICE/MACH (caspase-8), considered to be an upstream protease in the caspase cascade, and the downstream caspase CPP32/YAMA/Apopain (caspase-3) were activated, resulting in cleavage of the prototype substrate of caspases PARP. The broad-spectrum peptide inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone, which blocked cleavage of FLICE and PARP, also completely abrogated BA-triggered apoptosis. Cleavage of caspases was preceded by disturbance of mitochondrial membrane potential and by generation of reactive oxygen species. Overexpression of Bcl-2 and Bcl-XL conferred resistance to BA at the level of mitochondrial dysfunction, protease activation, and nuclear fragmentation. This suggested that mitochondrial alterations were involved in BA-induced activation of caspases. Furthermore, Bax and Bcl-xs, two death-promoting proteins of the Bcl-2 family, were up-regulated following BA treatment. Most importantly, neuroblastoma cells resistant to CD95- and doxorubicin-mediated apoptosis were sensitive to treatment with BA, suggesting that BA may bypass some forms of drug resistance. Because BA exhibited significant antitumor activity on patients' derived neuroblastoma cells ex vivo, BA may be a promising new agent for the treatment of neuroectodermal tumors in vivo.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Neuroblastoma/tratamiento farmacológico , Triterpenos/farmacología , Receptor fas/metabolismo , Antibióticos Antineoplásicos/farmacología , Apoptosis/genética , Caspasa 1 , Cisteína Endopeptidasas/metabolismo , Fragmentación del ADN , ADN de Neoplasias/efectos de los fármacos , Doxorrubicina/farmacología , Humanos , Mitocondrias/efectos de los fármacos , Proteínas de Neoplasias/metabolismo , Neuroblastoma/metabolismo , Neuroblastoma/patología , Triterpenos Pentacíclicos , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Células Tumorales Cultivadas/efectos de los fármacos , Proteína p53 Supresora de Tumor/metabolismo , Ácido Betulínico
14.
Oncogene ; 20(9): 1063-75, 2001 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-11314043

RESUMEN

Apoptosis in response to cellular stress such as treatment with cytotoxic drugs is mediated by effector caspases (caspase-3) which can be activated by different initiator pathways. Here, we report on a cell type specific triggering of death receptor and/or mitochondrial pathways upon drug treatment. In type I cells (BJAB), both the receptor and the mitochondrial pathway were activated upon drug treatment, since blockade of either the receptor pathway by overexpression of dominant negative FADD (FADD-DN) or of the mitochondrial pathway by overexpression of Bcl-X(L) only partially inhibited apoptosis. Drug treatment induced formation of a FADD- and caspase-8-containing CD95 death-inducing signaling complex (DISC) in type I cells resulting in activation of caspase-8 as the most apical caspase. In contrast, in type II cells (Jurkat), apoptosis was predominantly controlled by mitochondria, since overexpression of Bcl-2 completely blocked drug-induced apoptosis, while overexpression of FADD-DN had no protective effect. In these cells, caspases including caspase-8 were activated by mitochondria-driven signaling events and no DISC was detected despite expression levels of CD95, FADD and caspase-8 proteins comparable to type I cells. Likewise, drug-induced CD95 aggregation was predominantly found in type I cells. Bid was cleaved prior to mitochondrial alterations in type I cells providing a molecular link between caspase-8 activation and mitochondrial perturbations, whereas in type II cells, Bid was cleaved downstream of mitochondria. Our findings of a cell type specific response to cytotoxic drugs have implications for the identification of molecular parameters for chemosensitivity or resistance in different tumor cells.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Proteínas Portadoras/metabolismo , Doxorrubicina/farmacología , Células Jurkat/efectos de los fármacos , Mitocondrias/metabolismo , Receptor fas/metabolismo , Clorometilcetonas de Aminoácidos/farmacología , Proteína Proapoptótica que Interacciona Mediante Dominios BH3 , Western Blotting , Ácido Bongcréquico/farmacología , Inhibidores de Caspasas , Caspasas/metabolismo , Inhibidores de Cisteína Proteinasa/farmacología , Grupo Citocromo c/metabolismo , Resistencia a Medicamentos , Proteína de Dominio de Muerte Asociada a Fas , Expresión Génica/efectos de los fármacos , Humanos , Potenciales de la Membrana , Mutación , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/fisiología , Transducción de Señal/fisiología , Células Tumorales Cultivadas/efectos de los fármacos , Proteína bcl-X
15.
Cell Death Differ ; 11 Suppl 1: S73-85, 2004 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-15105835

RESUMEN

In chemosensitive leukemias and solid tumors, anticancer drugs have been shown to induce apoptosis. Deficiencies in the apoptotic pathways may lead to chemoresistance. Here we report that glutathione (GSH) plays a critical role in activation of apoptosis pathways by CD95 (APO-1/Fas) or anticancer drugs. Upon treatment with anticancer drugs or CD95 triggering, CD95-resistant or Bcl-x(L) overexpressing CEM cells were deficient in activation of apoptosis pathways. CD95-resistant and Bcl-x(L) overexpressing CEM cells exhibited higher intracellular GSH levels in comparison to parental cells. Downregulation of GSH by L-buthionine-(S,R)-sulfoxime (BSO), a specific inhibitor of glutathione synthesis, reversed deficiencies in activation of apoptosis pathways by anticancer drugs or CD95. Interestingly, downregulation of GSH by BSO increased CD95 DISC formation in type I cells. In hybrids of CD95-resistant cells with sensitive cells and hybrids of overexpressing Bcl-x(L) cells with sensitive cells, the phenotype of apoptosis resistance was dominant. Also, in these hybrids, downregulation of GSH reversed CD95- and chemoresistance. We conclude that dominant apoptosis resistance depends, at least in part, on intracellular GSH levels, which may affect apoptosis signaling at different compartments, for example, the death receptor or mitochondria.


Asunto(s)
Apoptosis/fisiología , Resistencia a Antineoplásicos/fisiología , Glutatión/fisiología , Anticuerpos Monoclonales/farmacología , Apoptosis/efectos de los fármacos , Proteína Proapoptótica que Interacciona Mediante Dominios BH3 , Butionina Sulfoximina/farmacología , Proteínas Portadoras/metabolismo , Caspasa 3 , Caspasa 8 , Caspasa 9 , Caspasas/metabolismo , Fusión Celular , Línea Celular Tumoral , Citocromos c/metabolismo , Proteínas Adaptadoras de Señalización del Receptor del Dominio de Muerte , Regulación hacia Abajo , Doxorrubicina/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Expresión Génica/efectos de los fármacos , Glutatión/metabolismo , Humanos , Células Híbridas/efectos de los fármacos , Células Híbridas/metabolismo , Potenciales de la Membrana/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Poli(ADP-Ribosa) Polimerasas/metabolismo , Proteínas/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/fisiología , Especies Reactivas de Oxígeno/metabolismo , Receptores del Factor de Necrosis Tumoral/análisis , Receptores del Factor de Necrosis Tumoral/metabolismo , Proteína Inhibidora de la Apoptosis Ligada a X , Proteína bcl-X , Receptor fas/inmunología , Receptor fas/fisiología
16.
Cell Death Differ ; 6(5): 471-80, 1999 May.
Artículo en Inglés | MEDLINE | ID: mdl-10381639

RESUMEN

Induction of CD95 ligand (CD95-L) may contribute to drug-induced apoptosis in chemosensitive leukemias and solid tumors. Here we report that induction of CD95-L and apoptosis by doxorubicin in leukemic and neuroblastoma cells is regulated by the redox state and reactive oxygen species (ROS). Preincubation of chemosensitive cells with antioxidants such as N-acetyl-cysteine (NAC) or glutathione (GSH), significantly reduced doxorubicin-induced apoptosis, hyperexpression of ROS, loss of mitochondrial membrane potential (DeltaPsim) and upregulation of CD95-L expression. Doxorubicin-resistant cells exhibited higher levels of GSH in comparison to chemosensitive cells and were deficient in hyperproduction of ROS, loss of DeltaPsim and upregulation of CD95-L in response to cytotoxic drugs. Downregulation of intracellular GSH concentrations reversed deficient drug-induced hyperproduction of ROS and CD95-L upregulation. In addition, overexpression of Bcl-XL in CEM cells blocked doxorubicin-triggered ROS and CD95-L expression. These findings suggest that induction of CD95-L by cytotoxic drugs is modulated by the cellular redox state and mitochondria derived ROS.


Asunto(s)
Apoptosis , Doxorrubicina/metabolismo , Glicoproteínas de Membrana/biosíntesis , Acetilcisteína/farmacología , Animales , Regulación hacia Abajo , Doxorrubicina/farmacología , Resistencia a Medicamentos , Proteína Ligando Fas , Glutatión/metabolismo , Glutatión/farmacología , Glicoproteínas de Membrana/genética , Oxidación-Reducción , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Células Tumorales Cultivadas , Proteína bcl-X , Receptor fas/metabolismo
17.
Leukemia ; 11(11): 1833-41, 1997 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-9369415

RESUMEN

The molecular mechanisms for sensitivity and resistance of tumor cells towards chemotherapy are only partially understood. In chemosensitive leukemias and solid tumors, anticancer drugs have been shown to induce apoptosis. We previously identified activation of the CD95 (APO-1/Fas) receptor/CD95 ligand (CD95/CD95-L) system as a key mechanism for drug-induced apoptosis. Here, we show that therapeutic concentrations of doxorubicin, methotrexate and cytarabine also induce apoptosis via activation of the CD95 system in primary leukemia cells in vivo. CD95-resistant and doxorubicin-resistant leukemia and neuroblastoma cells display cross-resistance for induction of cell death. Down-regulation of CD95 expression was found in drug-resistant and CD95-resistant cell lines. Furthermore, up-regulation of CD95-L, previously shown to mediate drug-induced apoptosis in a variety of tumor cells, was completely blocked in doxorubicin-resistant cells. The prototype caspase (ICE/Ced-3 protease) substrate, poly(ADP-ribose)polymerase (PARP), was cleaved in sensitive, but not in resistant tumor cells following CD95 triggering or drug treatment. Since failure to activate CD95-L was not due to decreased drug uptake or increased drug efflux, non-multi-drug resistance (non-MDR) mechanisms are involved in this type of resistance. These findings suggested that an intact CD95 system plays a key role in determining sensitivity or resistance towards anticancer therapy.


Asunto(s)
Antibióticos Antineoplásicos/farmacología , Apoptosis , Doxorrubicina/farmacología , Resistencia a Antineoplásicos , Leucemia-Linfoma de Células T del Adulto/metabolismo , Linfoma no Hodgkin/metabolismo , ARN Mensajero/efectos de los fármacos , Receptor fas/efectos de los fármacos , Western Blotting , Recuento de Células/efectos de los fármacos , Humanos , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Leucemia-Linfoma de Células T del Adulto/inmunología , Linfoma no Hodgkin/tratamiento farmacológico , Linfoma no Hodgkin/inmunología , ARN Mensajero/metabolismo , Células Tumorales Cultivadas/efectos de los fármacos , Receptor fas/inmunología , Receptor fas/metabolismo
18.
Leukemia ; 13(11): 1854-8, 1999 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-10557062

RESUMEN

Cytotoxic drugs commonly used in chemotherapy of leukemia and solid tumors have been shown to primarily act by inducing apoptosis in sensitive target cells. Apoptosis may involve activation of death-inducing ligand/receptor systems such as CD95 (APO-1/Fas). Treatment with anticancer drugs such as doxorubicin, methotrexate, cytarabine, etoposide and cisplatin at therapeutic concentrations leads to induction of CD95-ligand (CD95-L). CD95-L can mediate cell death in an autocrine/paracrine manner by crosslinking CD95 receptor (CD95). Interfering with CD95-ligand/receptor interaction by antagonistic antibodies to the receptor reduces sensitivity to drug-mediated apoptosis in some cell systems. In addition, treatment with cytotoxic drugs may result in upregulation of CD95, thereby increasing the sensitivity to the CD95 death signal. Apoptosis depends on activation of caspases. Deficient activation of the CD95 system was found in drug-resistant cells. In addition, CD95-resistant and doxorubicin-resistant cells displayed cross-resistance for induction of cell death. Thus, intact apoptosis pathways such as the CD95 system may play a role in determining sensitivity or resistance of tumor cells to chemotherapy.


Asunto(s)
Antineoplásicos/farmacología , Apoptosis , Neoplasias/metabolismo , Receptor fas/metabolismo , Resistencia a Antineoplásicos , Proteína Ligando Fas , Humanos , Glicoproteínas de Membrana/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Transducción de Señal/efectos de los fármacos
19.
Leukemia ; 13(3): 400-9, 1999 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-10086731

RESUMEN

The CD95 (APO-1/Fas) system plays an important role in lymphocyte homeostasis and contributes to anticancer drug-induced apoptosis in some tumor cells. Most childhood B-lineage ALL cells are constitutively resistant towards CD95-induced death. We report here that chemotherapeutic drugs, such as doxorubicin, cytarabine, methotrexate and 6-mercaptopurine, sensitize CD95-resistant pre-B-ALL cell lines for CD95- and lymphokine-activated killer (LAK)-induced cell death. Enhanced susceptibility in drug-treated cells was found to be associated with increased expression of CD95 mRNA and surface expression of CD95 protein, as well as loss of Bcl-xL protein and disturbance of mitochondrial function. Low level activation of caspases and cleavage of poly(ADP-ribose) polymerase following CD95 triggering was strongly increased in drug pre-treated cells. Furthermore, drug pre-treated cells could be rescued from CD95-mediated apoptosis by blocking the CD95-signaling pathway with a FADD-dominant negative expression construct. Our data suggest that chemotherapeutic drugs may sensitize pre-B ALL cells by at least two mechanisms: (1) by increasing CD95 expression; and (2) by lowering the threshold for apoptotic signals. These findings may explain the effectiveness of low-dose chemotherapy and indicate an active role for key molecules of apoptosis and the immune system during chemotherapy of leukemia.


Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Células Asesinas Activadas por Linfocinas/efectos de los fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Receptor fas/inmunología , Secuencia de Bases , Caspasas/metabolismo , Cartilla de ADN , Activación Enzimática , Humanos , Células Asesinas Activadas por Linfocinas/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Células Tumorales Cultivadas
20.
Leukemia ; 13(3): 410-8, 1999 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-10086732

RESUMEN

Killing of target cells by cytotoxic T cells is mediated by induction of apoptosis requiring functional death pathways. Kill is mediated either by the CD95 or the perforin/granzyme pathway. We found that SH-EP neuroblastoma cells are preferentially killed via CD95, while in the T leukemia cell line CEM CD95 and perforin/granzyme are involved. In both types of cell lines, cells resistant to CD95- and drug-induced apoptosis are crossresistant to cytotoxic T cell kill. Resistant cells show decreased apoptosis and deficient activation of caspases indicated by decreased cleavage of the prototype caspase substrate PARP. Preincubation with the caspase inhibitor zVAD-fmk strongly decreased LAK cell kill in sensitive cells. Although parental CEM cells could be sensitized for LAK kill by preincubation with doxorubicin, resistance could not be reverted in doxorubicin or CD95 resistant CEM cells. These data demonstrate the crossresistance in induction of apoptosis by different cytotoxic regimens in tumor cells and may have implications for the immunotherapy of tumors in which apoptosis resistance was induced by previous chemotherapy.


Asunto(s)
Resistencia a Antineoplásicos/inmunología , Linfocitos T Citotóxicos/inmunología , Células Cultivadas , Humanos , Células Tumorales Cultivadas
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