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1.
World J Urol ; 42(1): 305, 2024 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-38724829

RESUMEN

PURPOSE: Postoperative urinary retention (PUR) is a common complication after prostate enucleation, which leads to an increased length of hospital stay and decreased postoperative satisfaction. This study determined the predictive factors of postoperative urine retention within 1 month after prostate enucleation and investigated whether PUR influences surgical outcomes at the 2-week, 3-month, and 6-month follow-up time points. METHODS: Data were collected from the electronic medical records of 191 patients with benign prostatic obstruction (BPO) during October 2018 to September 2021. Of them, 180 patients who underwent thulium laser or plasma kinetic enucleation of the prostate (ThuLEP, PKEP) were separated into the PUR group (n = 24) and the non-PUR (NPUR) group (n = 156). Uroflowmetry and the International Prostate Symptom Score (IPSS) questionnaire were followed up at 2 weeks, 3 months, and 6 months postoperatively. RESULTS: The PUR group had a significantly higher percentage of patients with type 2 diabetes mellitus (DM) than the NPUR group. Postoperatively, compared with the NPUR group, the PUR group had significantly less improvement in changes in the IPSS Quality of Life scores at 2 weeks, the total IPSS(International Prostate Symptom Score) at all follow-up times, the IPSS-S(IPSS storage subscores) at 2 weeks and 3 months, and the IPSS-V(IPSS voiding subscores) at all follow-up times. Predictive factors for PUR include lower preoperative maximum urinary flow (Qmax), lower preoperative total IPSS, and higher operation time. CONCLUSION: Lower preoperative Qmax, lower IPSS scores, and longer operation time were risk factors for PUR. Furthermore, PUR could be a prognostic factor for prostatic enucleation surgical outcomes.


Asunto(s)
Complicaciones Posoperatorias , Prostatectomía , Hiperplasia Prostática , Retención Urinaria , Humanos , Masculino , Retención Urinaria/etiología , Retención Urinaria/epidemiología , Hiperplasia Prostática/cirugía , Anciano , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Persona de Mediana Edad , Prostatectomía/métodos , Prostatectomía/efectos adversos , Resultado del Tratamiento , Estudios Retrospectivos , Endoscopía
2.
Int Urol Nephrol ; 2024 Apr 02.
Artículo en Inglés | MEDLINE | ID: mdl-38564078

RESUMEN

OBJECTIVES: This study aims to investigate the surgical outcomes of endoscopic enucleation of the prostate in older males with or without preoperative urinary retention (UR). MATERIAL AND METHODS: We conducted a study on selected patients with symptomatic benign prostatic hyperplasia (BPH) who underwent either thulium:YAG laser (vela XL) prostate enucleation (ThuLEP) or bipolar plasma enucleation of the prostate (B-TUEP) at the geriatric urology department of our institution. The studied patients were categorized into two groups, namely the UR group and the non-UR group, on the basis of whether they experienced UR in the 1 month preceding their surgery. Their clinical outcomes following prostate endoscopic surgery were evaluated and analyzed. RESULTS: Our results revealed comparable outcomes for operation time, length of hospital stay, percentage of tissue removed, re-catheterization rate, and urinary tract infection rate within the 1 month between the B-TUEP and ThuLEP surgery groups, regardless of UR history. However, the non-UR B-TUEP group experienced more blood loss relative to the non-UR ThuLEP group (P = .004). Notably, patients with UR exhibited significantly greater changes in IPSS total, IPSS voiding, and prostate-specific antigen values relative to those without UR. CONCLUSIONS: Both ThuLEP and B-TUEP were effective in treating BPH-related bladder outlet obstruction. Our study identified more pronounced changes in IPSS total, IPSS voiding, and prostate-specific antigens within the UR group. Moreover, the rate of postoperative UR in this group was not higher than that observed in the non-UR group. Our study also revealed that the presumed benefits of laser surgery in reducing blood loss were less pronounced for patients with UR.

3.
Medicina (Kaunas) ; 59(11)2023 Oct 26.
Artículo en Inglés | MEDLINE | ID: mdl-38003945

RESUMEN

Background and Objectives: Urinary tract stones have long been a common ailment afflicting the population, with a high incidence and a wide distribution across different age groups. Effectively preventing the occurrence of urinary tract stones is of paramount importance. The primary aim of this study is to investigate the correlations between individual characteristics, water consumption habits, dietary habits, exercise habits, and the occurrence of urinary tract stones in a Taiwanese population. Materials and Methods: This study is cross-sectional research conducted over one month in 2022. One hundred eligible urinary stone cases were recruited through physician screening at outpatient clinics, and an additional one hundred samples from surgical outpatients without urinary tract stones were included as the control group. A questionnaire survey was employed to gather information on demographic variables, dietary habits, water consumption, and exercise habits of the cases. Descriptive statistics, chi-square tests, and logistic regression were used to explore the impact of relevant factors on urinary stone formation. Results: The analysis results revealed that among the demographic variables, males exhibited a higher risk of contracting urinary tract stones than females, and the majority of cases fell within the 40- to 49-year-old age group. Unhealthy lifestyle habits such as smoking and betel nut chewing also demonstrated a higher susceptibility to urinary tract stones. A logistic regression analysis showed that individuals who engaged in physical activity more than three times per week and those with inadequate water intakes had a higher risk of developing urinary tract stones. Conclusions: There is a close relationship between lifestyle and urinary tract stones. It is recommended that individuals continue to hydrate adequately during exercise.


Asunto(s)
Cálculos Urinarios , Masculino , Femenino , Humanos , Adulto , Persona de Mediana Edad , Estudios Transversales , Cálculos Urinarios/epidemiología , Cálculos Urinarios/etiología , Dieta/efectos adversos , Factores de Riesgo , Estilo de Vida
4.
Medicina (Kaunas) ; 59(8)2023 Jul 29.
Artículo en Inglés | MEDLINE | ID: mdl-37629685

RESUMEN

Background and Objectives: This study evaluated and compared the surgical outcomes of retrograde intrarenal surgery (RIRS) lithotripsy versus robot-assisted laparoscopic pyelolithotomy (RAPL) in community patients with renal pelvic stones larger than 2 cm. Materials and Methods: A total of 77 patients who underwent RIRS (RIRS group, n = 50) or RAPL (RAPL group, n = 27) at our institution between December 2016 and July 2022 were recruited. A single surgeon performed all surgical operations. Preoperative, operative, and postoperative data were recorded. The study evaluated various clinical outcomes, namely, urinary tract infections, analgesic use, emergency room readmissions, stone clearance rates, surgical complications, and medical expenditures associated with the treatment courses, and compared them between the groups. Results: The RAPL group had a larger mean stone diameter and higher degree of hydronephrosis than the RIRS group did. The RIRS group had superior outcomes regarding operative time, length of postoperative hospital stay, surgical wound pain, and medical expenditures. Regarding postoperative outcomes, comparable rates of postoperative urinary tract infection, prolonged analgesic use, and emergency room readmissions were observed between the groups. However, the RAPL group had a higher stone clearance rate than the RIRS group did (81.5% vs. 52.0%, p = 0.014). Conclusions: For the surgical treatment of renal pelvis stones larger than 2 cm, RAPL has a superior stone clearance rate than RIRS; however, RIRS achieves superior outcomes in terms of medical expenditures, length of hospital stay, and surgical wound pain. Both procedures were equally safe.


Asunto(s)
Cálculos Renales , Procedimientos Quirúrgicos Robotizados , Herida Quirúrgica , Humanos , Procedimientos Quirúrgicos Robotizados/efectos adversos , Ureteroscopía/efectos adversos , Cálculos Renales/cirugía , Pelvis Renal/cirugía , Dolor , Resultado del Tratamiento
5.
Diagnostics (Basel) ; 13(4)2023 Feb 06.
Artículo en Inglés | MEDLINE | ID: mdl-36832080

RESUMEN

Bleeding during endoscopic prostate surgery is often overlooked, and appropriate measurement techniques are rarely applied. We proposed a simple and convenient method for assessing the severity of bleeding during endoscopic prostate surgery. We determined the factors affecting bleeding severity and whether they affected the surgical results and functional outcomes. Records from March 2019 to April 2022 were obtained for selected patients who underwent endoscopic prostate enucleation through either 120-W Vela XL Thulium:YAG laser or bipolar plasma enucleation of the prostate. The bleeding index was measured using the following equation: irrigant hemoglobin (Hb) concentration (g/dL) × irrigation fluid volume (mL)/preoperative blood Hb concentration (g/dL) × enucleated tissue (g). Our research revealed that patients who underwent surgery employing the thulium laser, those aged over 80 years, and those with a preoperative maximal flow rate (Qmax) of more than 10 cc/s experienced less surgical bleeding. The patients' treatment outcomes differed depending on the severity of the bleeding. Enucleating prostate tissue was easier in the patients with less severe bleeding, who also had a lower risk of developing urinary tract infections and an improved Qmax.

6.
Ther Clin Risk Manag ; 18: 145-154, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35237038

RESUMEN

BACKGROUND AND PURPOSE: In this study, we compared patient outcomes between the 120-W thulium laser (Vela™XL) prostate enucleation (ThuLEP) and bipolar transurethral enucleation of the prostate (B-TUEP) techniques. METHODS: We excluded patients with concomitant prostate cancer and bladder cancer and prospectively analyzed patients with benign prostatic obstruction (BPO) who underwent ThuLEP and B-TUEP from October 2018 to January 2021 in our institution. Patients' demographics, comorbidities, prostate volumes, prostate-specific antigen (PSA) levels, and International Prostate Symptoms Score (IPSS) were recorded. Perioperative outcomes including intraoperative blood loss, prostate resection percentage of the transition zone, postoperative pain score (numeric rating scale, NRS), complications, changes in postoperative uroflowmetry parameters, IPSS, and the rate of reuse of BPH medications were also evaluated. RESULTS: The data of a total of 111 patients (ThuLEP: 49, B-TUEP: 62) met the inclusion criteria were collected and analyzed prospectively. Our results revealed no significant differences between ThuLEP and B-TUEP in terms of operation time, prostate tissue enucleated, and days of hospitalization. However, patients in the ThuLEP group reported less pain after surgery than those in the B-TUEP group, and a higher proportion of patients in the B-TUEP group returned to the emergency department due to complications within one month postoperatively, with hematuria being the main cause. No significant differences were observed between the groups in changes in uroflowmetry parameters and IPSS at 2 weeks, 3 months, and 6 months postoperatively. CONCLUSION: The efficacy of ThuLEP was comparable to that of B-TUEP in terms of maximal flow rate, voiding volume, IPSS, and quality of life. ThuLEP also had several advantages over B-TUEP, including less blood loss and less postoperative pain. Therefore, ThuLEP can be considered a treatment of choice for BPH/bladder outlet obstruction, specifically for patients with a bleeding tendency and fear of pain.

7.
Am J Mens Health ; 15(6): 15579883211064128, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34903071

RESUMEN

This study investigated and compared the surgical outcomes of using endoscopic enucleation (thulium: YAG laser and bipolar plasma; ThuLEP) with robotic-assisted simple prostatectomy (RASP) in the treatment of prostates larger than 80 cm3. Records were obtained for the period from January 2014 to December 2020 for selected patients with BPO who underwent RASP, ThuLEP, or bipolar transurethral enucleation of the prostate (B-TUEP). Patients were excluded if they had active malignant disease, neurogenic bladder, lower urinary tract syndrome for reasons other than BPO, and a history of prostate surgery. Data of 396 patients who underwent B-TUEP, ThuLEP, and RASP were examined. A total of 112 patients met the including criteria, 85 of whom (B-TUEP: 29; ThuLEP: 41; RASP: 15) completed the final visit. The mean operation time and duration of postoperative hospital stays in the RASP group were significantly longer than those of the B-TUEP and ThuLEP groups. Only 1 patient in the RASP group required blood transfusion. The RASP group was superior to the other groups in voiding improvement including Qmax and IPSS voiding score. The pain score of the ThuLEP group after surgery was significantly lower than that of the other two groups during hospitalization, whereas the QoL scores were identical between the three groups at 2 weeks, 3 months, and 6 months post operation. The rates of returning to ER within the first postoperative month did not differ significantly between the three groups, and all the reasons for return involved minor complications that required no additional invasive treatment. These three surgical methods (B-TUEP, ThuLEP, and RASP) are all effective and safe for treating prostates larger than 80 cm3, with each having its particular advantages. B-TUEP requires the shortest operation time, ThuLEP causes the lowest postoperative pain, and RASP results in superior voiding function improvement.


Asunto(s)
Hiperplasia Prostática , Procedimientos Quirúrgicos Robotizados , Humanos , Masculino , Próstata/cirugía , Prostatectomía , Hiperplasia Prostática/cirugía , Calidad de Vida , Resultado del Tratamiento
9.
Int J Cancer ; 142(10): 1986-1993, 2018 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-29250783

RESUMEN

The association of the risk of suicide with cancer at different time points after a new cancer diagnosis is unclear. This study explored the suicide hazard at different time points after a first cancer diagnosis during the 1-year period before suicide. This case-crossover study included 2,907 suicide cases from 2002 to 2012 in Taiwan and compared the odds of suicide risk at different time points during one year after any cancer diagnosis with self-matched periods. The 13th month preceding the suicide date was used as the control period, and the hazard period was the duration from the 1st to 12th month in the conditional logistic regression for case-crossover comparisons. Among major groups of cancers, group of lip, oral cavity and pharynx cancers tended to have higher risk of suicide than other groups of cancers. The first month of cancer diagnosis was associated with the highest risk of suicide compared with the 13th month before suicide. The odds ratio (OR) of suicide were significantly in the first six months after cancer diagnosis but declined afterwards. For example, the adjusted OR was 3.47 [95% confidence interval (CI) = 2.60-4.62] in the first month and 1.53 (95% CI = 1.11-2.12) in the sixth month following cancer diagnosis. These findings provide clinicians with a vital reference period during which sufficient support and necessary referral to mental health support should be provided to reduce the risk of suicide among patients with newly diagnosed cancer morbidity.


Asunto(s)
Neoplasias/epidemiología , Neoplasias/psicología , Suicidio/psicología , Suicidio/estadística & datos numéricos , Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/diagnóstico , Riesgo , Factores Socioeconómicos , Taiwán/epidemiología , Factores de Tiempo , Adulto Joven
10.
BMC Public Health ; 16: 623, 2016 07 22.
Artículo en Inglés | MEDLINE | ID: mdl-27448804

RESUMEN

BACKGROUND: Previous studies have stressed the importance of tobacco exposure for the mood disorders of depression and anxiety. Although a few studies have focused on perinatal women, none have specifically considered the effects of smoking and secondhand smoke exposure on perinatal suicidal ideation. Thus, this study aimed to investigate the relationships of smoking/secondhand smoke exposure status with suicidal ideation, depression, and anxiety from the first trimester to the first month post partum. METHODS: This cross-sectional study based on self-reported data was conducted at five hospitals in Taipei, Taiwan from July 2011 to June 2014. The questionnaire inquired about women's pregnancy history, sociodemographic information, and pre-pregnancy smoking and secondhand smoke exposure status, and assessed their suicidal ideation, depression, and anxiety symptoms. Logistic regression models were used for analysis. RESULTS: In the 3867 women in the study, secondhand smoke exposure was positively associated with perinatal depression and suicidal ideation. Compared with women without perinatal secondhand smoke exposure, women exposed to secondhand smoke independently exhibited higher risks for suicidal ideation during the second trimester (odds ratio (OR) = 7.63; 95 % confidence interval (CI) = 3.25-17.93) and third trimester (OR = 4.03; 95 % CI = 1.76-9.23). Women exposed to secondhand smoke had an increased risk of depression, especially those aged 26-35 years (OR = 1.71; 95 % CI = 1.27-2.29). CONCLUSIONS: Secondhand smoke exposure also considerably contributes to adverse mental health for women in perinatal periods, especially for the severe outcome of suicidal ideation. Our results strongly support the importance of propagating smoke-free environments to protect the health of perinatal women.


Asunto(s)
Trastorno Depresivo/epidemiología , Complicaciones del Embarazo/epidemiología , Ideación Suicida , Adolescente , Adulto , Estudios Transversales , Trastorno Depresivo/etiología , Trastorno Depresivo/psicología , Femenino , Humanos , Embarazo , Complicaciones del Embarazo/etiología , Complicaciones del Embarazo/psicología , Trimestres del Embarazo , Escalas de Valoración Psiquiátrica , Factores de Riesgo , Factores Socioeconómicos , Taiwán/epidemiología , Contaminación por Humo de Tabaco/efectos adversos , Adulto Joven
11.
J Med Chem ; 52(18): 5642-8, 2009 Sep 24.
Artículo en Inglés | MEDLINE | ID: mdl-19708661

RESUMEN

This study is aimed at the pharmacological exploitation of alpha-tocopheryl succinate (1) to develop potent antiadhesion agents. Considering the structural cooperativity between the phytyl chain and the carboxylic terminus in determining the antiadhesion activity, our structural optimization led to compound 5 ([2-(4,8-dimethyl-non-1-enyl)-2,5,7,8-tetramethyl-chroman-6-yloxy]-acetic acid), which exhibited an-order-of-magnitude higher potency than 1 in blocking the adhesion of 4T1 metastatic breast cancer cells to extracellular matrix proteins (IC(50), 0.6 microM versus 10 microM). Evidence indicates that the ability of compound 5 to block cell adhesion and migration was attributable to its effect on disrupting focal adhesion and actin cytoskeletal integrity by facilitating the degradation of focal adhesion kinase. Interactions between tumor cells and the ECM in the tumor microenvironment have been increasingly recognized as critical modulators of the metastatic potential of tumor cells. Consequently, the ability of compound 5 to block such interactions provides a unique pharmacological tool to shed light onto mechanisms that govern cell adhesion and tumor metastasis.


Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Neoplasias de la Mama/patología , alfa-Tocoferol/química , alfa-Tocoferol/farmacología , Animales , Adhesión Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Descubrimiento de Drogas , Proteína-Tirosina Quinasas de Adhesión Focal/antagonistas & inhibidores , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Humanos , Concentración 50 Inhibidora , Ratones , Metástasis de la Neoplasia , Seudópodos/efectos de los fármacos , Seudópodos/metabolismo
12.
Mol Cancer Ther ; 7(4): 800-8, 2008 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-18413793

RESUMEN

Tamoxifen is a mainstay in the treatment of estrogen receptor (ER)-positive breast cancer patients. Although the efficacy of tamoxifen has been attributed to induction of tumor cell growth arrest and apoptosis by inhibition of ER signaling, recent evidence indicates that tamoxifen possesses ER-independent antitumor activities. Here, we use OSU-03012, a small-molecule inhibitor of phosphoinositide-dependent protein kinase-1 (PDK-1) to address the hypothesis that PDK-1/Akt signaling represents a therapeutically relevant target to sensitize ER-negative breast cancer to tamoxifen. OSU-03012 sensitized both ER-positive MCF-7 and ER-negative MDA-MB-231 cells to the antiproliferative effects of tamoxifen in an ER-independent manner. Flow cytometric analysis of phosphatidylserine externalization revealed that this augmented suppression of cell viability was attributable to a marked enhancement of tamoxifen-induced apoptosis by OSU-03012. Mechanistically, this OSU-03012-mediated sensitization was associated with suppression of a transient tamoxifen-induced elevation of Akt phosphorylation and enhanced modulation of the functional status of multiple Akt downstream effectors, including FOXO3a, GSK3alpha/beta, and p27. The growth of established MDA-MB-231 tumor xenografts was suppressed by 50% after oral treatment with the combination of tamoxifen (60 mg/kg) and OSU-03012 (100 mg/kg), whereas OSU-03012 and tamoxifen alone suppressed growth by 30% and 0%, respectively. These findings indicate that the inhibition of PDK-1/Akt signaling to sensitize ER-negative breast cancer cells to the ER-independent antitumor activities of tamoxifen represents a feasible approach to extending the use of tamoxifen to a broader population of breast cancer patients. Considering the urgent need for novel therapeutic strategies for ER-negative breast cancer patients, this combinatorial approach is worthy of continued investigation.


Asunto(s)
Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Receptor alfa de Estrógeno/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Pirazoles/uso terapéutico , Sulfonamidas/uso terapéutico , Tamoxifeno/uso terapéutico , Proteínas Quinasas Dependientes de 3-Fosfoinosítido , Animales , Apoptosis , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proliferación Celular/efectos de los fármacos , Supervivencia Celular , Resistencia a Antineoplásicos , Sinergismo Farmacológico , Femenino , Citometría de Flujo , Proteína Forkhead Box O3 , Factores de Transcripción Forkhead/metabolismo , Humanos , Immunoblotting , Ratones , Ratones Desnudos , Ovariectomía , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Células Tumorales Cultivadas
13.
Mol Pharmacol ; 70(5): 1534-41, 2006 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-16887935

RESUMEN

Although trastuzumab has been successfully used in patients with HER2-overexpressing metastatic breast cancer, resistance is a common problem that ultimately culminates in treatment failure. In light of the importance of Akt signaling in trastuzumab's antitumor action, we hypothesized that concurrent inhibition of Akt could enhance trastuzumab sensitivity and moreover reverse the resistant phenotype in HER2-positive breast cancer cells. Based on our finding that celecoxib mediates antitumor effects through the inhibition of phosphoinositide-dependent kinase-1 (PDK-1)/Akt signaling independently of cyclooxygenase-2 (COX-2), we used celecoxib as a scaffold to develop a COX-2-inactive PDK-1 inhibitor, 2-amino-N-[4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-acetamide (OSU-03012). Here, we investigated the effect of OSU-03012 on trastuzumab-mediated apoptosis in four breast cancer cell lines with different HER2 expression and trastuzumab-resistance status, including MDA-MB-231, BT474, SKBR3, and insulin-like growth factor-I receptor-overexpressing SKBR3 (SKBR3/IGF-IR). Effects of trastuzumab and OSU-03012, individually or in combination, on cell viability and changes in pertinent biomarkers including HER2 expression, phosphorylation of Akt, p27(kip1), and the PDK-1 substrate p70(S6K) were assessed. OSU-03012 alone was able to trigger apoptosis in all cell lines with equal potency (IC(50) = 3-4 microM), suggesting no cross-resistance with trastuzumab. Medium dose-effect analysis indicates that OSU-03012 potentiated trastuzumab's antiproliferative effect in HER2-positive cells, especially in SKBR3/IGF-IR cells, through the down-regulation of PDK-1/Akt signaling. This synergy, however, was not observed in HER2-negative MDA-MB-231 cells. This combination treatment represents a novel strategy to increase the efficacy of trastuzumab and to overcome trastuzumab resistance in the treatment of HER2-positive breast cancer.


Asunto(s)
Anticuerpos Monoclonales/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Resistencia a Antineoplásicos , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirazoles/farmacología , Receptor ErbB-2/metabolismo , Sulfonamidas/farmacología , Proteínas Quinasas Dependientes de 3-Fosfoinosítido , Anticuerpos Monoclonales Humanizados , Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica , Apoptosis/efectos de los fármacos , Celecoxib , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Sinergismo Farmacológico , Expresión Génica , Humanos , Fenotipo , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptor IGF Tipo 1/metabolismo , Trastuzumab , Regulación hacia Arriba/efectos de los fármacos
14.
J Biol Chem ; 280(46): 38879-87, 2005 Nov 18.
Artículo en Inglés | MEDLINE | ID: mdl-16186112

RESUMEN

Despite advances in understanding the role of histone deacetylases (HDACs) in tumorigenesis, the mechanism by which HDAC inhibitors mediate antineoplastic effects remains elusive. Modifications of the histone code alone are not sufficient to account for the antitumor effect of HDAC inhibitors. The present study demonstrates a novel histone acetylation-independent mechanism by which HDAC inhibitors cause Akt dephosphorylation in U87MG glioblastoma and PC-3 prostate cancer cells by disrupting HDAC-protein phosphatase 1 (PP1) complexes. Of four HDAC inhibitors examined, trichostatin A (TSA) and HDAC42 exhibit the highest activity in down-regulating phospho-Akt, followed by suberoylanilide hydroxamic acid, whereas MS-275 shows only a marginal effect at 5 microm. This differential potency parallels the respective activities in inducing tubulin acetylation, a non-histone substrate for HDAC6. Evidence indicates that this Akt dephosphorylation is not mediated through deactivation of upstream kinases or activation of downstream phosphatases. However, the effect of TSA on phospho-Akt can be rescued by PP1 inhibition but not that of protein phosphatase 2A. Immunochemical analyses reveal that TSA blocks specific interactions of PP1 with HDACs 1 and 6, resulting in increased PP1-Akt association. Moreover, we used isozyme-specific small interfering RNAs to confirm the role of HDACs 1 and 6 as key mediators in facilitating Akt dephosphorylation. The selective action of HDAC inhibitors on HDAC-PP1 complexes represents the first example of modulating specific PP1 interactions by small molecule agents. From a clinical perspective, identification of this PP1-facilitated dephosphorylation mechanism underscores the potential use of HDAC inhibitors in lowering the apoptosis threshold for other therapeutic agents through Akt down-regulation.


Asunto(s)
Inhibidores Enzimáticos/farmacología , Inhibidores de Histona Desacetilasas , Histonas/química , Apoptosis , Ciclo Celular , Línea Celular Tumoral , Supervivencia Celular , Relación Dosis-Respuesta a Droga , Regulación hacia Abajo , Histonas/metabolismo , Humanos , Ácidos Hidroxámicos/farmacología , Immunoblotting , Inmunohistoquímica , Inmunoprecipitación , Toxinas Marinas , Ácido Ocadaico/farmacología , Oxazoles/farmacología , Fosfatidilinositoles/química , Fosfoproteínas Fosfatasas/metabolismo , Fosforilación , Unión Proteica , Isoformas de Proteínas , Proteína Fosfatasa 1 , Proteína Fosfatasa 2 , Estructura Terciaria de Proteína , Proteínas Proto-Oncogénicas c-akt/metabolismo , Piranos/farmacología , ARN Interferente Pequeño/metabolismo , Serina/química , Transducción de Señal , Compuestos de Espiro/farmacología , Fracciones Subcelulares/metabolismo , Treonina/química , Factores de Tiempo
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