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1.
J Natl Compr Canc Netw ; 22(5)2024 01 08.
Artículo en Inglés | MEDLINE | ID: mdl-38190801

RESUMEN

Immune checkpoint inhibitors (ICIs) have transformed the treatment paradigm for many cancer types. The clinical use of ICIs is increasing rapidly, including in combinations associated with increased risk of toxicities, termed "immune-related adverse events" (irAEs). Therefore, MD Anderson Cancer Center (MDACC) in Houston, Texas has proactively responded by developing a priority endeavor known as the Immuno-Oncology Toxicity (IOTOX) initiative. This strategic initiative aims to facilitate the seamless integration of key domains: (1) standardized clinical practice and innovative decision toolsets; (2) patient and provider education; and (3) a comprehensive clinical and translational research platform. The ultimate goal of this initiative is to develop and disseminate clinical best practices and biologic insights into irAEs to improve outcomes of patients with irAEs at MDACC and in the wider oncology community.


Asunto(s)
Inhibidores de Puntos de Control Inmunológico , Neoplasias , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Neoplasias/terapia , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/terapia , Texas , Inmunoterapia/métodos , Inmunoterapia/efectos adversos
2.
Invest New Drugs ; 40(1): 99-105, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34468905

RESUMEN

BACKGROUND: Preclinical studies have shown that the combined inhibition of EGFR and NF-kB pathways to target the RalB/TBK1 pathway led to synergistic antitumor activity. Based on this rationale, we conducted a Phase I dose-escalation study combining the EGFR inhibitor erlotinib with the NF-kB inhibitor ixazomib in advanced solid tumors. Patients and methods. Patients with advanced solid tumors were eligible. The bayesian optimal interval phase I dose escalation design was used to establish the maximum tolerated dose and recommended phase 2 dose (RP2D). Results. Nineteen patients with a range of solid tumors were enrolled. The most common treatment-related adverse events of any grade were diarrhea (42.1%, 8/19), followed by rash (36.8%, 7/19) and nausea (21.1%, 4/19). The combination RP2D for oral ixazomib was 4.0 mg on days 1, 8, and 15 of a 28-day cycle, with oral erlotinib 150 mg daily. While no patient achieved RECIST v1.1 objective responses, 3 patients with advanced sarcoma experienced durable RECIST v1.1 stable disease ≥ 6 months (8.4, 10.6, and 15.7 months) and the best response was -13% decrease in clear cell sarcoma. Conclusions. The combination of erlotinib and ixazomib was safe and well tolerated among patients with advanced cancer, with preliminary signals of antitumor activity in patients with advanced sarcoma.


Asunto(s)
Antineoplásicos/uso terapéutico , Compuestos de Boro/uso terapéutico , Clorhidrato de Erlotinib/uso terapéutico , Glicina/análogos & derivados , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Compuestos de Boro/administración & dosificación , Compuestos de Boro/efectos adversos , Relación Dosis-Respuesta a Droga , Receptores ErbB/antagonistas & inhibidores , Clorhidrato de Erlotinib/administración & dosificación , Clorhidrato de Erlotinib/efectos adversos , Femenino , Glicina/administración & dosificación , Glicina/efectos adversos , Glicina/uso terapéutico , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , FN-kappa B/antagonistas & inhibidores
3.
Carcinogenesis ; 35(8): 1691-7, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24451148

RESUMEN

Speckle-type POZ protein (SPOP) is an adaptor of the cullin 3-based ubiquitin ligase responsible for the degradation of oncoproteins frequently overexpressed in many tumor cells. Altered expression and somatic mutations of SPOP have been observed in various tumor types with chromosomal aberrations, indicating a role of SPOP in maintaining genome stability, although a detailed mechanism remains unclear. Here, we show that SPOP is a component of the DNA damage response (DDR). SPOP is recruited to DNA double-strand break sites and it forms nuclear foci after DNA damage. SPOP foci colocalize with γ-H2AX foci and are predominantly dependent on the activity of the ataxia-telangiectasia mutated (ATM) kinase. Furthermore, SPOP interacts with ATM in response to DNA damage. Finally, we demonstrate that knocking down of SPOP resulted in an impaired DDR and a hypersensitivity to ionizing irradiation. Together, we highlight a critical role of SPOP in the DDR.


Asunto(s)
Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Daño del ADN/genética , Neoplasias/genética , Neoplasias/patología , Proteínas Nucleares/metabolismo , Proteínas Represoras/metabolismo , Apoptosis/fisiología , Apoptosis/efectos de la radiación , Western Blotting , Proliferación Celular/fisiología , Proliferación Celular/efectos de la radiación , Daño del ADN/efectos de la radiación , Técnica del Anticuerpo Fluorescente , Humanos , Inmunoprecipitación , Neoplasias/metabolismo , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Nucleares/genética , ARN Mensajero/genética , ARN Interferente Pequeño/genética , Radiación Ionizante , Reacción en Cadena en Tiempo Real de la Polimerasa , Proteínas Represoras/antagonistas & inhibidores , Proteínas Represoras/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Tumorales Cultivadas , Ensayo de Tumor de Célula Madre
4.
Biochim Biophys Acta ; 1833(6): 1489-97, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23470959

RESUMEN

The DEAD box protein family member DDX3 was previously identified as an inhibitor of death receptor-mediated extrinsic apoptotic signaling. However, there had been no studies of the role of DDX3 in regulating the other major type of apoptosis, intrinsic apoptotic signaling, which was examined here. Intrinsic apoptosis was induced in MCF-7 cells by treatment with staurosporine, a general kinase inhibitor, thapsigargin, which induces endoplasmic reticulum (ER) stress, and camptothecin, which causes DNA damage. Each of these treatments caused time-dependent activation of caspase-7, the predominant executioner caspase in these cells. Depletion of DDX3 using shRNA did not alter apoptotic responses to staurosporine or thapsigargin. However, caspase-7 activation induced by camptothecin was regulated by DDX3 in a manner dependent on the functional status of p53. Depletion of DDX3 abrogated camptothecin-induced caspase-7 activation in MCF-7 cells expressing functional wild-type p53, but oppositely potentiated camptothecin-mediated caspase activation in cells expressing mutant or non-functional p53, which was accompanied by increased activation of the extrinsic apoptotic signaling initiator caspase-8. In MCF-7 cells, depletion of DDX3 reduced by more than 50% camptothecin-induced p53 accumulation, and this effect was blocked by inhibition of the proteasome with MG132, indicating that DDX3 regulates p53 not at expression level but rather its stabilization after DNA damage. Co-immunoprecipitation experiments demonstrated that DDX3 associates with p53, and overexpression of DDX3 was sufficient to double the accumulation of p53 in the nucleus after DNA damage. Thus, DDX3 associates with p53, increases p53 accumulation, and positively regulates camptothecin-induced apoptotic signaling in cells expressing functional wild-type p53, whereas in cells expressing mutant or non-functional p53 DDX3 inhibits activation of the extrinsic apoptotic pathway to reduce caspase activation. These results demonstrate that DDX3 not only regulates extrinsic apoptotic signaling, as previously reported, but also selectively regulates intrinsic apoptotic signaling following DNA damage.


Asunto(s)
Apoptosis , Neoplasias de la Mama/patología , ARN Helicasas DEAD-box/metabolismo , Daño del ADN/genética , Proteína p53 Supresora de Tumor/metabolismo , Antineoplásicos Fitogénicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Camptotecina/farmacología , Caspasas/metabolismo , Inhibidores Enzimáticos/farmacología , Femenino , Humanos , Immunoblotting , Inmunoprecipitación , Transducción de Señal/efectos de los fármacos , Estaurosporina/farmacología , Células Tumorales Cultivadas
5.
Cancers (Basel) ; 16(2)2024 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-38254858

RESUMEN

Understanding of immune-related adverse events (irAEs) has evolved rapidly, and management guidelines are continually updated. We explored temporal changes in checkpoint inhibitor-induced irAE management at a tertiary cancer care center to identify areas for improvement. We conducted a single-center retrospective study of patients who developed a gastrointestinal, pulmonary, renal, or cardiac irAE between July and 1 October in 2019 or 2021. We collected patient demographic and clinical information up to 1 year after toxicity. Endoscopic evaluation and specialty follow-up after discharge for patients with gastrointestinal irAEs declined between the 2019 and 2021 periods. Symptom duration and steroid taper attempts also declined. For pulmonary irAEs, rates of specialty consultation, hospital admission and readmission, and mortality improved in 2021 compared with 2019. Follow-up rates after hospital discharge were consistently low (<50%) in both periods. For cardiac irAEs, consultation with a cardiologist was frequent and prompt in both periods. Outpatient treatment and earlier specialty consultation improved outcomes with gastrointestinal irAEs. Our study exploring irAE practice changes over time identified areas to improve management; specifically, timely specialty consultation was associated with better outcomes for gastrointestinal irAEs. These findings can help improve the quality of management algorithms at our institution and may inform policies in other institutions.

6.
Biochim Biophys Acta ; 1813(3): 438-47, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21237216

RESUMEN

DDX3, a DEAD box protein family member, appears to promote the progression of some cancers, which may partly result from its impedance of death receptor-mediated apoptosis. We found that another mechanism by which DDX3 may aid cancer progression is by promoting increased levels of the transcription factor Snail. Snail represses expression of cellular adhesion proteins, leading to increased cell migration and metastasis of many types of cancer. Knockdown of DDX3 levels by shRNA reduced basal levels of Snail in HeLa and MCF-7 cells, and this was associated with reduced cell proliferation and migration. Snail protein and mRNA levels were increased by treatment with the HDAC inhibitors sodium butyrate or trichostatin A, and these increases were attenuated in cells with DDX3 knocked down. Treatment of cells with camptothecin was discovered to increase Snail protein levels, and this increase was diminished in cells with DDX3 knocked down. Analysis of 31 patient glioblastoma multiforme (GBM) samples revealed a significant correlation between the levels of DDX3 and Snail. Thus, DDX3 is required for basal Snail expression and increases in Snail induced by HDAC inhibitors or camptothecin, indicating that this action of DDX3 may contribute to its promotion of the progression of some cancers.


Asunto(s)
ARN Helicasas DEAD-box/metabolismo , Regulación Neoplásica de la Expresión Génica , Neoplasias/metabolismo , Factores de Transcripción/metabolismo , Animales , Camptotecina/farmacología , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , ARN Helicasas DEAD-box/genética , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patología , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Masculino , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Neoplasias/genética , Neoplasias/patología , Factores de Transcripción de la Familia Snail , Inhibidores de Topoisomerasa/farmacología , Factores de Transcripción/genética
7.
Cancer Res ; 77(19): 5313-5326, 2017 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-28807937

RESUMEN

Chromophobe renal cell carcinoma (ChRCC) is characterized by major changes in chromosomal copy number (CN). No model is available to precisely elucidate the molecular drivers of this tumor type. HNF1B is a master regulator of gene expression. Here, we report that the transcription factor HNF1B is downregulated in the majority of ChRCC and that the magnitude of HNF1B loss is unique to ChRCC. We also observed a strong correlation between reduced HNF1B expression and aneuploidy in ChRCC patients. In murine embryonic fibroblasts or ACHN cells, HNF1B deficiency reduced expression of the spindle checkpoint proteins MAD2L1 and BUB1B, and the cell-cycle checkpoint proteins RB1 and p27. Furthermore, it altered the chromatin accessibility of Mad2l1, Bub1b, and Rb1 genes and triggered aneuploidy development. Analysis of The Cancer Genome Atlas database revealed TP53 mutations in 33% of ChRCC where HNF1B expression was repressed. In clinical specimens, combining HNF1B loss with TP53 mutation produced an association with poor patient prognosis. In cells, combining HNF1B loss and TP53 mutation increased cell proliferation and aneuploidy. Our results show how HNF1B loss leads to abnormal mitotic protein regulation and induction of aneuploidy. We propose that coordinate loss of HNF1B and TP53 may enhance cellular survival and confer an aggressive phenotype in ChRCC. Cancer Res; 77(19); 5313-26. ©2017 AACR.


Asunto(s)
Carcinoma de Células Renales/patología , Proteínas de Ciclo Celular/metabolismo , Factor Nuclear 1-beta del Hepatocito/metabolismo , Neoplasias Renales/patología , Proteínas Mad2/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Aneuploidia , Animales , Apoptosis , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/metabolismo , Ciclo Celular , Proteínas de Ciclo Celular/genética , Proliferación Celular , Células Cultivadas , Inestabilidad Cromosómica , Embrión de Mamíferos/citología , Embrión de Mamíferos/metabolismo , Fibroblastos/citología , Fibroblastos/metabolismo , Factor Nuclear 1-beta del Hepatocito/genética , Humanos , Neoplasias Renales/genética , Neoplasias Renales/metabolismo , Proteínas Mad2/genética , Ratones , Proteínas Serina-Treonina Quinasas/genética
8.
Cancer Immunol Res ; 3(9): 1017-29, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26014097

RESUMEN

Renal cell carcinoma (RCC) is an immunogenic and proangiogenic cancer, and antiangiogenic therapy is the current mainstay of treatment. Patients with RCC develop innate or adaptive resistance to antiangiogenic therapy. There is a need to identify biomarkers that predict therapeutic resistance and guide combination therapy. We assessed the interaction between antiangiogenic therapy and the tumor immune microenvironment and determined their impact on clinical outcome. We found that antiangiogenic therapy-treated RCC primary tumors showed increased infiltration of CD4(+) and CD8(+) T lymphocytes, which was inversely related to patient overall survival and progression-free survival. Furthermore, specimens from patients treated with antiangiogenic therapy showed higher infiltration of CD4(+)FOXP3(+) regulatory T cells and enhanced expression of checkpoint ligand programed death-ligand 1 (PD-L1). Both immunosuppressive features were correlated with T-lymphocyte infiltration and were negatively related to patient survival. Treatment of RCC cell lines and RCC xenografts in immunodeficient mice with sunitinib also increased tumor PD-L1 expression. Results from this study indicate that antiangiogenic treatment may both positively and negatively regulate the tumor immune microenvironment. These findings generate hypotheses on resistance mechanisms to antiangiogenic therapy and will guide the development of combination therapy with PD-1/PD-L1-blocking agents.


Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Carcinoma de Células Renales/secundario , Resistencia a Antineoplásicos/inmunología , Neoplasias Renales/tratamiento farmacológico , Microambiente Tumoral/inmunología , Inhibidores de la Angiogénesis/farmacología , Animales , Antineoplásicos/farmacología , Antígeno B7-H1/biosíntesis , Bevacizumab/farmacología , Biomarcadores de Tumor/biosíntesis , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/inmunología , Xenoinjertos , Humanos , Tolerancia Inmunológica , Indoles/farmacología , Neoplasias Renales/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Ratones Desnudos , Trasplante de Neoplasias , Pirroles/farmacología , Sunitinib , Subgrupos de Linfocitos T/inmunología , Linfocitos T Reguladores/inmunología , Células Tumorales Cultivadas , Microambiente Tumoral/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos
9.
Yao Xue Xue Bao ; 37(3): 161-4, 2002 Mar.
Artículo en Zh | MEDLINE | ID: mdl-12579752

RESUMEN

AIM: In order to discover new inhibitors and enhancers of nitric oxide synthase (NOS), an in vitro assay to determine NOS activity was established for high throughput screening. METHODS: The activity of NOS was detected based on the change of nicotinamide-adenine dinucleotide phosphate (NADPH) concentration in the reaction system by the fluorescence density. The enzyme was prepared from bovine brain by gradient centrifugation. The reaction performed in black 96 well micro-plate with a final volume of 90 microL. Every factor which would affect the results such as the concentration of NADPH, L-arginine (L-Arg, used as substrate) and enzyme protein was optimized in different conditions. At last, 5,600 samples (compounds and extracts) were screened by the method. RESULTS: The test signal (fluorescence density) in the reaction system was influenced by many different factors such as temperature and concentration of substrates. The ideal system contains protein 1.50 mg.mL-1, L-Arg 1 mmol.L-1, NADPH 0.1 mmol.L-1 at 37 degrees C. In this method, there were about 2% samples which emit fluorescence, and about 0.5% samples which quench the fluorescence. So these samples were deleted from the sample library. The effects of these samples on activity of NOS were distributed in a normal manner. About 2% samples had potential effects on the NOS activity (including inhibitors and enhancers). CONCLUSION: The method can be performed by high throughput screening and gives the stable data, not only for inhibitors, but also for enhancers of NOS activity.


Asunto(s)
Evaluación Preclínica de Medicamentos/métodos , Inhibidores Enzimáticos/aislamiento & purificación , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/metabolismo , Animales , Arginina/farmacología , Bovinos , Inhibidores Enzimáticos/farmacología , Técnicas In Vitro , NADP/farmacología , Nitroarginina/farmacología
10.
Cancer Res ; 74(11): 3127-36, 2014 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-24755468

RESUMEN

Aberrant von Hippel Lindau (VHL) protein function is the underlying driver of VHL-related diseases, including both sporadic and inherited clear cell renal cell carcinoma (ccRCC). About one third of VHL mutations are missense point mutations, with R167Q being the most common VHL point mutation in hereditary VHL disease. Although it has been studied extensively, the ability of VHL-R167Q to downregulate hypoxia-inducible factor 2α (HIF2α) is still controversial. In addition, the manner in which the mutation contributes to tumorigenesis is not fully understood. No therapeutic approach is available to target VHL-R167Q and similar missense point mutations. We analyzed VHL-R167Q proteostasis and function at normoxia, at hypoxia with different oxygen pressure, and in a xenograft mouse model. We showed that the protein levels of VHL-R167Q dictate its ability to downregulate HIF2α and suppress tumor growth. Strikingly, the proteasome inhibitors bortezomib and carfilzomib, which are currently in clinical use, stabilize VHL-R167Q and increase its ability to downregulate HIF2α. VHL-R167Q binds elongin C and elongin B with considerably less avidity than wild-type VHL does but retains residual capacity to generate a VHL-elongin C-elongin B complex, downregulate HIF2α, and suppress tumorigenesis, which could be rescued by increase of VHL-R167Q levels. Finally, we used in silico approaches and identified other missense VHL mutants in addition to VHL-R167Q that might be rescued by similar strategies. Thus, our studies revealed detailed information describing how VHL-R167Q contributes to tumorigenesis and identified a potential targeted therapy for ccRCC and other VHL-related disease in patients carrying VHL-R167Q or similar missense mutations.


Asunto(s)
Proteínas Mutantes/genética , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genética , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Carcinogénesis/genética , Línea Celular Tumoral , Proteínas de Unión al ADN/genética , Regulación hacia Abajo , Elonguina , Humanos , Ratones , Ratones Desnudos , Mutación Missense , Complejo de la Endopetidasa Proteasomal/genética , Factores de Transcripción/genética
11.
J Mol Cell Biol ; 4(5): 304-15, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22923499

RESUMEN

The DNA damage response (DDR) is critical for the maintenance of genetic stability and serves as an anti-cancer barrier during early tumorigenesis. However, the role of the DDR in tumor progression and metastasis is less known. Here, we demonstrate that the ATM kinase, one of the critical DDR elements, is hyperactive in late stage breast tumor tissues with lymph-node metastasis and this hyperactivity correlates with elevated expression of the epithelial-mesenchymal transition marker, Snail. At the molecular level, we demonstrate that ATM regulates Snail stabilization by phosphorylation on Serine-100. Using mass spectrometry, we identified HSP90 as a critical binding protein of Snail in response to DNA damage. HSP90 binds to and stabilizes phosphorylated Snail. We further provide in vitro and in vivo evidence that activation of ATM-mediated Snail phosphorylation promotes tumor invasion and metastasis. Finally, we demonstrate that Snail Serine-100 phosphorylation is elevated in breast cancer tissues with lymph-node metastasis, indicating clinical significance of the ATM-Snail pathway. Together, our findings provide strong evidence that the ATM-Snail pathway promotes tumor metastasis, highlighting a previously undescribed role of the DDR in tumor invasion and metastasis.


Asunto(s)
Neoplasias de la Mama/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas de Unión al ADN/metabolismo , Metástasis Linfática/patología , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal , Factores de Transcripción/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Animales , Proteínas de la Ataxia Telangiectasia Mutada , Neoplasias de la Mama/genética , Proteínas de Ciclo Celular/genética , Línea Celular Tumoral , Daño del ADN , Proteínas de Unión al ADN/genética , Femenino , Células HeLa , Humanos , Ratones , Ratones Endogámicos BALB C , Proteínas Serina-Treonina Quinasas/genética , Factores de Transcripción de la Familia Snail , Factores de Transcripción/genética , Proteínas Supresoras de Tumor/genética
12.
Radiat Oncol ; 6: 39, 2011 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-21496273

RESUMEN

BACKGROUND: Perifosine is a membrane-targeted alkylphospholipid developed to inhibit the PI3K/Akt pathway and has been suggested as a favorable candidate for combined use with radiotherapy. In this study, we investigated the effect of the combined treatment of perifosine and radiation (CTPR) on prostate cancer cells in vitro and on prostate cancer xenografts in vivo. METHODS: Human prostate cancer cell line, CWR22RV1, was treated with perifosine, radiation, or CTPR. Clonogenic survival assays, sulforhodamine B cytotoxity assays and cell density assays were used to assess the effectiveness of each therapy in vitro. Measurements of apoptosis, cell cycle analysis by flow cytometry and Western blots were used to evaluate mechanisms of action in vitro. Tumor growth delay assays were used to evaluate radiation induced tumor responses in vivo. RESULTS: In vitro, CTPR had greater inhibitory effects on prostate cancer cell viability and clonogenic survival than either perifosine or radiation treatment alone. A marked increase in prostate cancer cell apoptosis was noted in CTPR. Phosphorylation of AKT-T308 AKT and S473 were decreased when using perifosine treatment or CTPR. Cleaved caspase 3 was significantly increased in the CTPR group. In vivo, CTPR had greater inhibitory effects on the growth of xenografts when compared with perifosine or radiation treatment alone groups. CONCLUSIONS: Perifosine enhances prostate cancer radiosensitivity in vitro and in vivo. These data provide strong support for further development of this combination therapy in clinical studies.


Asunto(s)
Fosforilcolina/uso terapéutico , Neoplasias de la Próstata/radioterapia , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Animales , Apoptosis/efectos de la radiación , Línea Celular Tumoral/efectos de la radiación , Proliferación Celular/efectos de la radiación , Humanos , Masculino , Ratones , Ratones Desnudos , Fosforilcolina/farmacocinética , Fármacos Sensibilizantes a Radiaciones/farmacocinética , Resultado del Tratamiento
13.
Cell Signal ; 21(12): 1857-65, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19698783

RESUMEN

This study examined if there are interactions between two key proteins that oppositely regulate intrinsic apoptosis, X-linked inhibitor of apoptosis protein (XIAP), a key suppressor of apoptosis that binds to inhibit active caspases, and glycogen synthase kinase-3 (GSK3), which promotes intrinsic apoptosis. Immunoprecipitation of GSK3beta revealed that XIAP associates with GSK3beta, as do two other members of the IAP family, cIAP-1, and cIAP-2. Cell fractionation revealed that XIAP is predominantly cytosolic, cIAP-1 is predominantly nuclear and nearly all of the nuclear cIAP-1 and cIAP-2 are associated with GSK3. Expression of individual domains of XIAP demonstrated that the RING domain of XIAP associates with GSK3. Inhibition of GSK3 did not alter the binding of XIAP to active caspase-9 or caspase-3 after stimulation of apoptosis with staurosporine. However, inhibition of GSK3 reduced apoptosis and apoptosome formation, including the recruitments of caspase-9 and XIAP to Apaf-1, in response to staurosporine treatment. Cell free measurements of apoptosome-induced caspase-3 activation demonstrated that GSK3 acts upstream of the apoptosome to facilitate intrinsic apoptotic signaling. This facilitation was blocked by overexpression of XIAP. These findings indicate that the RING domain of XIAP (and probably cIAP-1 and cIAP-2) associates with GSK3, GSK3 acts upstream of the apoptosome to promote intrinsic apoptosis, and the association between XIAP and GSK3 may block the pro-apoptotic function of GSK3.


Asunto(s)
Apoptosis , Glucógeno Sintasa Quinasa 3/metabolismo , Proteína Inhibidora de la Apoptosis Ligada a X/metabolismo , Caspasas/metabolismo , Línea Celular Tumoral , Regulación de la Expresión Génica , Glucógeno Sintasa Quinasa 3/análisis , Glucógeno Sintasa Quinasa 3 beta , Células HeLa , Humanos , Litio/metabolismo , Unión Proteica , Estructura Terciaria de Proteína , Fracciones Subcelulares/química , Proteína Inhibidora de la Apoptosis Ligada a X/análisis , Proteína Inhibidora de la Apoptosis Ligada a X/genética
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