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1.
Oncology ; : 1-11, 2024 Jul 17.
Artículo en Inglés | MEDLINE | ID: mdl-38952143

RESUMEN

INTRODUCTION: Avelumab (Ave) is approved for metastatic urothelial carcinoma (mUC) maintenance therapy and prolongs overall survival (OS). We explored trends related to Ave treatment of mUC patients. METHODS: A total of 72 patients with mUC treated with first-line chemotherapy, from January 2019 to November 2022, at our affiliated institutions, were analyzed. We compared clinical parameters and the prognosis of patients treated with Ave (n = 43) because of progression during first-line chemotherapy, with untreated patients (Ave-untreated; n = 29). Among the Ave-treated group, we classified patients showing a complete or partial response or stable disease in their best response to Ave maintenance therapy as Ave-suitable patients; these were retrospectively analyzed. Potential prognostic factors, including the Geriatric Nutritional Risk Index (GNRI) for determining patients suitable for Ave, were evaluated. RESULTS: The basic clinical parameters of patients when first-line treatment was initiated were not statistically different between the two groups. The Ave-suitable group (median 26.6 months, 95% confidence interval [CI]: 19.4-not reached [NR]) showed significantly longer median OS after first-line treatment than the Ave-untreated group (median 12.0 months, 95% CI: 7.5-NR) with tolerable adverse events. The cut-off values of prognostic factors were set by the receiver operating characteristic curve. Low age and GNRI sustainability were revealed as significant prognostic factors for being Ave-suitable both in univariate and multivariate analysis. CONCLUSION: In mUC, Ave maintenance prolonged OS within tolerable safety profiles. GNRI sustainability may be used as a biomarker to predict being Ave-suitable.

2.
Arch Toxicol ; 98(12): 4143-4158, 2024 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-39269499

RESUMEN

Fullerene whiskers (FLW)s are thin rod-like structures composed of C60 and C70 fullerene (FL). The shape of FLWs suggests potential toxic effects including carcinogenicity to the lung and pleura, similar to effects elicited by asbestos and multi-walled carbon nanotubes (MWCNT)s. However, no long-term carcinogenic studies of FL or FLW have been conducted. In the present study we investigated the pulmonary and pleural carcinogenicity of FL and FLW. Twelve-week-old male F344 rats were administered 0.25 or 0.5 mg FL, FLW, MWCNT-7, and MWCNT-N by intra-tracheal intra-pulmonary spraying (TIPS). Acute lung lesions and carcinogenicity were analyzed at 1 and 104 weeks after 8 doses/15 days TIPS administration. At week 1, FLW, MWCNT-7, and MWCNT-N significantly increased alveolar macrophage infiltration. Expression of Ccl2 and Ccl3, reactive oxygen species production, and cell proliferation were significantly increased by administration of MWCNT-7 and MWCNT-N but not FL or FLW. At week 104, the incidence of bronchiolo-alveolar adenoma plus adenocarcinoma was significantly increased in the MWCNT-7 and MWCNT-N groups, and the incidence of mesothelioma was significantly increased in the MWCNT-7 group. No significant induction of pulmonary or pleural tumorigenesis was observed in the FL or FLW groups. The number of 8-OHdG-positive cells in the alveolar epithelium was significantly increased in the MWCNT-7 and MWCNT-N groups but not in the FL or FLW groups. FL and FLW did not exert pulmonary or pleural carcinogenicity in our study. In addition, oxidative DNA damage was implicated in MWCNT-induced lung carcinogenesis, suggesting that it may be a useful initial marker of carcinogenicity.


Asunto(s)
Fulerenos , Neoplasias Pulmonares , Pulmón , Ratas Endogámicas F344 , Especies Reactivas de Oxígeno , Animales , Fulerenos/toxicidad , Fulerenos/administración & dosificación , Masculino , Pulmón/efectos de los fármacos , Pulmón/patología , Especies Reactivas de Oxígeno/metabolismo , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/patología , Nanotubos de Carbono/toxicidad , Ratas , Neoplasias Pleurales/inducido químicamente , Neoplasias Pleurales/patología , Proliferación Celular/efectos de los fármacos , Quimiocina CCL2/metabolismo , Quimiocina CCL3/metabolismo , Macrófagos Alveolares/efectos de los fármacos , Carcinógenos/toxicidad , Carcinógenos/administración & dosificación , Pleura/efectos de los fármacos , Pleura/patología , Pruebas de Carcinogenicidad , Administración por Inhalación
3.
Clin Exp Nephrol ; 27(4): 382-391, 2023 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-36689033

RESUMEN

BACKGROUND: Acute kidney injury (AKI) is a common complication of cardiac surgeries. The incidence of AKI after cardiac surgeries using cardiopulmonary bypass (CPB-AKI) is high, emphasizing the need to determine strategies to prevent CPB-AKI. This study investigates the correlation between CPB-AKI and trace metal levels in clinical and animal studies. METHODS: Samples and clinical data were obtained from 74 patients from the Nagoya City University Hospital and Okazaki City Hospital. Blood samples were collected before, immediately after, and 2 h after CPB withdrawal. Trace metal levels were measured using inductively coupled plasma mass spectrometry. Sr or vehicle treatment was orally administered to the rats to determine if Sr was associated with CPB-AKI. After the treatment, ischemia-reperfusion (IR) injury was induced, and serum creatinine (SCr) and blood urea nitrogen (BUN) levels were measured. RESULTS: In this clinical study, the incidence of CPB-AKI was found to be 28% (21/74). The body mass index and estimated glomerular filtration rate were significantly different in patients with AKI. The intensive care unit and hospital stay were longer in AKI patients than in non-AKI patients. The Na, Fe, and Sr levels were significantly higher in AKI patients before CPB. Also, Fe and Sr were higher immediately after CPB withdrawal, and Sr was higher 2 h after CPB withdrawal in AKI patients. Animal studies showed that Sr-treated rats had significantly increased SCr and BUN levels than vehicle-treated rats at 24 h post-IR injury. CONCLUSIONS: High preoperative serum Sr levels may be associated with CPB-AKI.


Asunto(s)
Lesión Renal Aguda , Procedimientos Quirúrgicos Cardíacos , Daño por Reperfusión , Animales , Ratas , Puente Cardiopulmonar/efectos adversos , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Tasa de Filtración Glomerular , Lesión Renal Aguda/epidemiología , Lesión Renal Aguda/etiología , Nitrógeno de la Urea Sanguínea , Creatinina , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Biomarcadores
4.
Oncology ; 100(8): 429-438, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35760062

RESUMEN

INTRODUCTION: This study had two objectives: (i) to evaluate oncological outcomes in a long-term follow-up of patients with bladder cancer after reduced-port laparoscopic radical cystectomy (RP-LRC) and (ii) to assess the effect of modified Glasgow prognostic scores (mGPS) on patient outcomes. METHODS: Consecutive patients (n = 100) who received RP-LRC between March 2012 and December 2018 at our institution and affiliated hospital were retrospectively reviewed. Preoperative serum albumin and C-reactive protein levels were determined. Patients were grouped based on clinical T stage (≤cT2: n = 75, ≥cT3: n = 25) using pooled cumulative data. Oncological outcomes and mGPS as a prognostic biomarker were analyzed retrospectively. Kaplan-Meier curves displayed recurrence and survival rates. Univariate and multivariate Cox regression analyses evaluated potential prognostic factors for recurrence-free survival (RFS) and cancer-specific survival (CSS). RESULTS: Patient characteristics between the two groups were statistically similar for preoperative hematological and mGPS status, blood loss level, rate of allogeneic transfusion, and pneumoperitoneum time. After a median follow-up period of 55 months, 40/100 patients experienced disease relapse. RFS and CSS for ≤cT2 were significantly less than for ≥cT3 (p < 0.001, p < 0.05, respectively). Distant metastasis occurred in 30 patients with similar distributions of relapse sites between T-stage cohorts. Median RFS for mGPS 1/2 were 18.9 (95% confidence interval [CI]: 8.8-not assessed [NA]) and 35.0 (95% CI: 8.7-NA) months, respectively, significantly worse than for mGPS 0 (median NA, 95% CI: NA-NA); CSS was similar. Univariate and multivariate analyses revealed ≥cT3 stage, worse clinical N stage, and poor mGPS status were significant prognostic factors for short RFS and CSS. CONCLUSIONS: A large proportion of bladder cancer patients who undergo RP-LRC experience relapse, with ≥cT3 stage, worse clinical N stage or poor mGPS status identified as significant prognostic factors. Our findings may contribute to improved surgical procedures for such patients.


Asunto(s)
Laparoscopía , Neoplasias de la Vejiga Urinaria , Cistectomía/efectos adversos , Estudios de Seguimiento , Humanos , Laparoscopía/métodos , Recurrencia Local de Neoplasia/cirugía , Pronóstico , Estudios Retrospectivos , Resultado del Tratamiento , Neoplasias de la Vejiga Urinaria/patología
5.
J Pharmacol Sci ; 149(2): 53-59, 2022 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-35512855

RESUMEN

Podocyte injury is responsible for nephrotic syndrome. Previously, we found that tadalafil, a phosphodiesterase 5 inhibitor, might have protective effects on podocytes. Here, we investigated the effects of tadalafil in a nephrotic syndrome model and human podocyte cells. We divided adriamycin (ADR)-induced nephrotic syndrome model rats into the following groups: control + vehicle, control + tadalafil, ADR + vehicle, and ADR + tadalafil. The tadalafil-treated groups were orally administered 10 mg/kg tadalafil for 2 weeks. Renal parameters were measured. Immunohistology and immunofluorescence assays of glomerular injury were performed. Human primary podocytes were treated with or without tadalafil, and ADR. Cell viability and permeability assays were performed. ADR + vehicle exhibited severe proteinuria compared with control + vehicle and control + tadalafil. ADR + tadalafil attenuated proteinuria compared with ADR + vehicle. Wilms' tumor 1 (WT1) immunostaining revealed that the number of WT1-positive cells was decreased by ADR; however, this decrease was prevented by ADR + tadalafil. In human podocytes, tadalafil increased the viability of ADR-treated cells, which was abrogated by KT5823, a cGMP-dependent protein kinase (PKG) inhibitor. Moreover, tadalafil prevented albumin permeability in ADR-treated cells. ADR treatment alone increased the permeability of albumin compared with the control. Tadalafil might inhibit kidney injury progression by preventing damage to podocytes and dysfunction of the glomerular filtration barrier.


Asunto(s)
Síndrome Nefrótico , Podocitos , Albúminas/efectos adversos , Albúminas/metabolismo , Animales , Doxorrubicina/efectos adversos , Femenino , Humanos , Masculino , Síndrome Nefrótico/inducido químicamente , Síndrome Nefrótico/tratamiento farmacológico , Síndrome Nefrótico/metabolismo , Podocitos/patología , Proteinuria/inducido químicamente , Proteinuria/tratamiento farmacológico , Ratas , Tadalafilo/farmacología , Tadalafilo/uso terapéutico
6.
Hepatol Res ; 52(1): 93-104, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-34038612

RESUMEN

AIM: The microRNA (miR) clusters miR-183/96/182 and miR-217/216a/216b are significantly upregulated in nonviral hepatocellular carcinoma (NBNC-HCC). Here, we investigate the impact of each member of these clusters on the clinical outcome of NBNC-HCC and analyze the antitumor effects of miR-96-5p. METHODS: The association between recurrence-free survival of 111 NBNC-HCC patients and the levels of miR-183-5p, miR-96-5p, miR-182-5p, miR-217-5p, miR-216a-5p, and miR-216b-5p in tumor and adjacent tissues was investigated. The impact of miR-96-5p on apoptosis and invasion of a hepatoma cell line, HepG2, was investigated by cell counting, Transwell assay, and flow cytometry, respectively. RESULTS: MicroRNA-183-5p, miR-96-5p, miR-182-5p, miR-217-5p, and miR-216b-5p were significantly upregulated in tumor tissues compared to the adjacent tissues (p = 0.0005, p = 0.0030, p = 0.0002, p = 0.0011, and p = 0.0288, respectively). By multivariate Cox regression analysis, high tumor/adjacent ratios of miR-182-5p (p = 0.007) and miR-217-5p (p = 0.008) were associated with poor recurrence-free survival. In contrast, a low tumor/adjacent ratio of miR-96-5p (p < 0.001) was associated with poor recurrence-free survival. It suggested that further upregulation of miR-96-5p in tumors might have an inhibitory effect on recurrence. Transfection of miR-96-5p mimic significantly induced apoptosis of HepG2 cells, in association with downregulation of Nucleophosmin 1 (NPM1) and a decrease of phosphorylated AKT protein. Interestingly, simultaneous knockdown of the NPM1 and AKT genes induced apoptosis. MicroRNA-96-5p also suppressed proliferation and invasion, which inhibited epithelial-to-mesenchymal transition of HCC cells. CONCLUSION: MicroRNA-96-5p as a tumor suppressor would be valuable to stratify NBNC-HCC patients at high risk of recurrence.

7.
Mol Cell ; 55(1): 73-84, 2014 Jul 03.
Artículo en Inglés | MEDLINE | ID: mdl-24910096

RESUMEN

Senescence is a state of permanent growth arrest and is a pivotal part of the antitumorigenic barrier in vivo. Although the tumor suppressor activities of p53 and pRb family proteins are essential for the induction of senescence, molecular mechanisms by which these proteins induce senescence are still not clear. Using time-lapse live-cell imaging, we demonstrate here that normal human diploid fibroblasts (HDFs) exposed to various senescence-inducing stimuli undergo a mitosis skip before entry into permanent cell-cycle arrest. This mitosis skip is mediated by both p53-dependent premature activation of APC/C(Cdh1) and pRb family protein-dependent transcriptional suppression of mitotic regulators. Importantly, mitotic skipping is necessary and sufficient for senescence induction. p16 is only required for maintenance of senescence. Analysis of human nevi also suggested the role of mitosis skip in in vivo senescence. Our findings provide decisive evidence for the molecular basis underlying the induction and maintenance of cellular senescence.


Asunto(s)
Senescencia Celular , Mitosis/fisiología , Puntos de Control del Ciclo Celular , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Fibroblastos/citología , Fibroblastos/metabolismo , Humanos , Modelos Biológicos , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/fisiología , Imagen de Lapso de Tiempo , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/fisiología
8.
Part Fibre Toxicol ; 19(1): 30, 2022 04 22.
Artículo en Inglés | MEDLINE | ID: mdl-35449069

RESUMEN

BACKGROUND: Considering the expanding industrial applications of carbon nanotubes (CNTs), safety assessment of these materials is far less than needed. Very few long-term in vivo studies have been carried out. This is the first 2-year in vivo study to assess the effects of double walled carbon nanotubes (DWCNTs) in the lung and pleura of rats after pulmonary exposure. METHODS: Rats were divided into six groups: untreated, Vehicle, 3 DWCNT groups (0.12 mg/rat, 0.25 mg/rat and 0.5 mg/rat), and MWCNT-7 (0.5 mg/rat). The test materials were administrated by intratracheal-intrapulmonary spraying (TIPS) every other day for 15 days. Rats were observed without further treatment until sacrifice. RESULTS: DWCNT were biopersistent in the rat lung and induced marked pulmonary inflammation with a significant increase in macrophage count and levels of the chemotactic cytokines CCL2 and CCL3. In addition, the 0.5 mg DWCNT treated rats had significantly higher pulmonary collagen deposition compared to the vehicle controls. The development of carcinomas in the lungs of rats treated with 0.5 mg DWCNT (4/24) was not quite statistically higher (p = 0.0502) than the vehicle control group (0/25), however, the overall incidence of lung tumor development, bronchiolo-alveolar adenoma and bronchiolo-alveolar carcinoma combined, in the lungs of rats treated with 0.5 mg DWCNT (7/24) was statistically higher (p < 0.05) than the vehicle control group (1/25). Notably, two of the rats treated with DWCNT, one in the 0.25 mg group and one in the 0.5 mg group, developed pleural mesotheliomas. However, both of these lesions developed in the visceral pleura, and unlike the rats administered MWCNT-7, rats administered DWCNT did not have elevated levels of HMGB1 in their pleural lavage fluids. This indicates that the mechanism by which the mesotheliomas that developed in the DWCNT treated rats is not relevant to humans. CONCLUSIONS: Our results demonstrate that the DWCNT fibers we tested are biopersistent in the rat lung and induce chronic inflammation. Rats treated with 0.5 mg DWCNT developed pleural fibrosis and lung tumors. These findings demonstrate that the possibility that at least some types of DWCNTs are fibrogenic and tumorigenic cannot be ignored.


Asunto(s)
Neoplasias Pulmonares , Mesotelioma , Nanotubos de Carbono , Animales , Exposición por Inhalación/efectos adversos , Pulmón , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/patología , Mesotelioma/patología , Nanotubos de Carbono/toxicidad , Pleura , Ratas
9.
Int J Clin Oncol ; 27(1): 165-174, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-34633579

RESUMEN

BACKGROUND: After first-line chemotherapy failure, metastatic urothelial carcinoma (mUC) patients undergo pembrolizumab (PEM) or gemcitabine and docetaxel (GD) therapy. We retrospectively investigated outcomes of second-line GD or PEM for mUC patients. METHODS: A total of 198 mUC patients from Nagoya City University and affiliated hospitals who received second-line treatment were grouped according to immune check point inhibitor (ICI) availability: Groups A (pre-ICI: n = 104) and B (post-ICI: n = 94). We compared clinical outcomes using Kaplan-Meier curves. Univariate and multivariate Cox regression analyses assessed potential prognostic factors for overall survival (OS). RESULTS: Median OS was significantly longer for Group B [median 13.6 months, 95% confidence interval (CI): 7.6-17.6] than A (7.6 months, 5.3-8.8). By sub-group analysis, patients received no additional treatment (Naïve, n = 70), or PEM or GD (Salvage, n = 24) in Group B, with median OS of Naïve and A groups similar. Compared to the Salvage group, significant differences in OS were observed (median 7.6 months, 95% CI 5.3-8.8; Group A, 7.6 months, 4.7-13.8; Naïve, 25.7 months, 14.0-31.0; p < 0.01). For the Salvage group, OS for sequential treatment of GD-salvage PEM and PEM-salvage GD patients was similar (p = 0.10). Multivariate analysis showed a low neutrophil-to-lymphocyte ratio (NLR) and high geriatric nutritional risk index (GNRI) as significant prognostic factors affecting long OS [95% CI 1.12-3.45, hazard ratio (HR): 1.97; 95% CI 0.24-0.71, 0.41, respectively]. CONCLUSION: Second-line GD or PEM therapy for mUC patients showed equivalent survival benefits. GNRI and NLR are prognostic biomarkers for survival outcome.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Anciano , Carcinoma de Células Transicionales/tratamiento farmacológico , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Docetaxel/uso terapéutico , Humanos , Estudios Retrospectivos , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Gemcitabina
10.
Carcinogenesis ; 42(7): 940-950, 2021 07 16.
Artículo en Inglés | MEDLINE | ID: mdl-33640964

RESUMEN

The 5-year survival rate of pancreatic ductal carcinoma (PDAC) patients is <10% despite progress in clinical medicine. Strategies to prevent the development of PDAC are urgently required. The flavonoids Luteolin (Lut) and hesperetin (Hes) may be cancer-chemopreventive, but effects on pancreatic carcinogenesis in vivo have not been studied. Here, the chemopreventive effects of Lut and Hes on pancreatic carcinogenesis are assessed in the BOP-induced hamster PDAC model. Lut but not Hes suppressed proliferation of pancreatic intraepithelial neoplasia (PanIN) and reduced the incidence and multiplicity of PDAC in this model. Lut also inhibited the proliferation of hamster and human pancreatic cancer cells in vitro. Multi-blot and microarray assays revealed decreased phosphorylated STAT3 (pSTAT3) and dihydropyrimidine dehydrogenase (DPYD) on Lut exposure. To explore the relationship between DPYD and STAT3 activity, the former was silenced by RNAi or overexpressed using expression vectors, and the latter was inactivated by small molecule inhibitors or stimulated by IL6 in human PDAC cells. DPYD knock-down decreased, and overexpression increased, pSTAT3 and cell proliferation. DPYD expression was decreased by inactivation of STAT3 and increased by its activation. The frequency of pSTAT3-positive cells and DPYD expression was significantly correlated and was decreased in parallel by Lut in the hamster PDAC model. Finally, immunohistochemical analysis in 73 cases of human PDAC demonstrated that DPYD expression was positively correlated with the Ki-67 labeling index, and high expression was associated with poor prognosis. These results indicate that Lut is a promising chemopreventive agent for PDAC, targeting a novel STAT3-DPYD pathway.


Asunto(s)
Carcinoma Ductal Pancreático/tratamiento farmacológico , Dihidrouracilo Deshidrogenasa (NADP)/antagonistas & inhibidores , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Luteolina/farmacología , Neoplasias Pancreáticas/tratamiento farmacológico , Factor de Transcripción STAT3/metabolismo , Anciano , Animales , Apoptosis , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Proliferación Celular , Cricetinae , Femenino , Humanos , Masculino , Ratones , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Pronóstico , Factor de Transcripción STAT3/genética , Tasa de Supervivencia , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
11.
Int J Mol Sci ; 22(14)2021 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-34299067

RESUMEN

Pancreatic cancer is a fatal disease, and thus its chemoprevention is an important issue. Based on the recent report that patients with allergic diseases have a low risk for pancreatic cancer, we examined the potential chemopreventive effect of anti-allergic agents using a hamster pancreatic carcinogenesis model. Among the three anti-allergic drugs administered, montelukast showed a tendency to suppress the incidence of pancreatic cancer. Further animal study revealed a significantly decreased incidence of pancreatic cancer in the high-dose montelukast group compared with controls. The development of the pancreatic intraepithelial neoplasia lesions was also significantly suppressed. The Ki-67 labeling index was significantly lower in pancreatic carcinomas in the high-dose montelukast group than in controls. In vitro experiments revealed that montelukast suppressed proliferation of pancreatic cancer cells in a dose-dependent manner with decreased expression of phospho-ERK1/2. Montelukast induced G1 phase arrest. Conversely, leukotriene D4 (LTD4), an agonist of CYSLTR1, increased cellular proliferation of pancreatic cancer cells with an accumulation of phospho-ERK1/2. In our cohort, pancreatic ductal adenocarcinoma patients with high CYSLTR1 expression showed a significantly unfavorable clinical outcome compared with those with low expression. Our results indicate that montelukast exerts a chemopreventive effect on pancreatic cancer via the LTD4-CYSLTR1 axis and has potential for treatment of pancreatic carcinogenesis.


Asunto(s)
Acetatos/farmacología , Antiasmáticos/farmacología , Proliferación Celular , Ciclopropanos/farmacología , Leucotrieno D4/metabolismo , Nitrosaminas/toxicidad , Neoplasias Pancreáticas/tratamiento farmacológico , Quinolinas/farmacología , Receptores de Leucotrienos/metabolismo , Sulfuros/farmacología , Animales , Carcinógenos/toxicidad , Cricetinae , Humanos , Masculino , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Células Tumorales Cultivadas
12.
Carcinogenesis ; 41(8): 1145-1157, 2020 08 12.
Artículo en Inglés | MEDLINE | ID: mdl-31805186

RESUMEN

A need exists for seeking effective treatments for castration-resistant prostate cancer (CRPC) in response to its emergence following androgen deprivation therapy as a major clinical problem. In the present study, we investigated the chemopreventive and chemotherapeutic potential of luteolin, a flavonoid with antioxidative properties, on prostate cancer, including CRPC. Luteolin inhibited the progression of rat prostate carcinogenesis by induction of apoptosis in a transgenic rat for adenocarcinoma of prostate (TRAP) model. Luteolin decreased cell proliferation in a dose-dependent manner and induced apoptosis with the activation of caspases 3 and 7 in both rat (PCai1, established from a TRAP prostate tumor) and human (22Rv1) CRPC cells. Dietary luteolin also suppressed tumor growth via an increase in apoptosis and inhibition of angiogenesis in PCai1 and 22Rv1 xenografts implanted in castrated nude mice. We also focused on androgen receptor splice variant 7 (AR-V7), which contributes to cell proliferation and therapeutic resistance in CRPC. Luteolin dramatically suppressed AR-V7 protein expression in 22Rv1 cells in vitro and ex vivo. Microarray analysis identified MiR-8080, which contains a possible target sequence for AR-V7 3'-UTR, as a gene upregulated by luteolin. MiR-8080 transfection decreased the AR-V7 expression level and the induction of apoptosis in 22Rv1 cells. Furthermore, miR-8080 knockdown canceled luteolin decreasing AR-V7 and the cell growth of 22Rv1. MiR-8080 induced by luteolin intake enhanced the therapeutic effect of enzalutamide on 22Rv1 xenografts under castration conditions. These results indicate luteolin inhibits CRPC by AR-V7 suppression through miR-8080, highlighting luteolin and miR-8080 as promising therapeutic agents for this disease.


Asunto(s)
Antagonistas de Receptores Androgénicos/farmacología , Antioxidantes/farmacología , Luteolina/farmacología , MicroARNs/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Receptores Androgénicos/metabolismo , Antagonistas de Receptores Androgénicos/uso terapéutico , Animales , Antioxidantes/uso terapéutico , Apoptosis/efectos de los fármacos , Carcinogénesis/efectos de los fármacos , Caspasa 3/metabolismo , Caspasa 7/metabolismo , Línea Celular Tumoral , Quimioprevención , Humanos , Luteolina/uso terapéutico , Masculino , Ratones , Ratones Desnudos , MicroARNs/genética , Neovascularización Patológica/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/prevención & control , Isoformas de Proteínas/antagonistas & inhibidores , Ratas , Ratas Sprague-Dawley , Ratas Transgénicas , Receptores Androgénicos/genética , Ensayos Antitumor por Modelo de Xenoinjerto
13.
Cancer Sci ; 111(4): 1165-1179, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-31994822

RESUMEN

Luteolin is a natural flavonoid with strong anti-oxidative properties that is reported to have an anti-cancer effect in several malignancies other than bladder cancer. In this study, we describe the effect of luteolin on a human bladder cancer cell line, T24, in the context of the regulation of p21, thioredoxin-1 (TRX1) and the mechanistic target of rapamycin (mTOR) pathway. Luteolin inhibited cell survival and induced G2/M cell-cycle arrest, p21 upregulation and downregulation of phospho(p)-S6, which is downstream of mTOR signaling. Luteolin also upregulated TRX1 and reduced intracellular reactive oxygen species production. In a subcutaneous xenograft mouse model using the rat bladder cancer cell line, BC31, tumor volumes were significantly decreased in mice orally administered luteolin compared to control. Immunohistochemical analysis revealed that increased p21 and decreased p-S6 expression were induced in the luteolin treatment group. Moreover, in another in vivo N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced rat bladder cancer model, the oral administration of luteolin led to a trend of decreased bladder tumor dimension and significantly decreased the Ki67-labeling index and p-S6 expression. Furthermore, the major findings on the metabolism of luteolin suggest that both plasma and urine luteolin-3'-O-glucuronide concentrations are strongly associated with the inhibition of cell proliferation and mTOR signaling. Moreover, a significant decrease in the squamous differentiation of bladder cancer is attributed to plasma luteolin-3'-glucuronide concentration. In conclusion, luteolin, and in particular its metabolized product, may represent another natural product-derived therapeutic agent that acts against bladder cancer by upregulating p21 and inhibiting mTOR signaling.


Asunto(s)
Luteolina/farmacología , Serina-Treonina Quinasas TOR/genética , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Proteínas de Unión al GTP rho/genética , Animales , Apoptosis/efectos de los fármacos , Butilhidroxibutilnitrosamina/toxicidad , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Antígeno Ki-67/genética , Luteolina/metabolismo , Masculino , Ratones , Proteínas Proto-Oncogénicas c-akt/genética , Ratas , Transducción de Señal/efectos de los fármacos , Tiorredoxinas/genética , Neoplasias de la Vejiga Urinaria/inducido químicamente , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patología , Ensayos Antitumor por Modelo de Xenoinjerto
14.
Neurourol Urodyn ; 39(7): 1922-1929, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32725853

RESUMEN

AIMS: To investigate the effect of anagliptin (Ana), a dipeptidyl peptidase-4 (DPP-4) inhibitor, on acute ischemia-induced bladder dysfunction in rats. METHODS: Eight-week-old female Wistar-ST rats were randomly assigned into four groups: (a) sham; (b) ligation (Lig); (c) Lig + Ana; and (d) Lig + Liraglutide (a glucagon-like peptide-1 [GLP-1] receptor agonist; Lira). Rats in the Lig, Lig + Ana, and Lig + Lira groups underwent ligature of the bilateral internal iliac arteries. Ana was orally administered mixed with the CE-2 diet. Lira was subcutaneously administered once a day. Blood glucose levels, plasma dipeptidyl peptidase 4 (DPP-4) activity, GLP-1 levels, and bladder function were measured in all groups. Bladder blood flow was measured in the sham, Lig, and Lig + Ana groups, 4 weeks postsurgery. RESULTS: No differences in blood glucose levels among the groups were observed. DPP-4 activity decreased in the Lig + Ana group (P < .01). GLP-1 levels in the Lig + Ana and Lig + Lira groups were higher than those in the sham and Lig groups (P < .01). Intercontraction intervals (ICIs) were longer in the Lig and Lig + Lira groups than in the sham group (P < .05), but similar to those observed in the Lig + Ana and sham groups. The Lig group exhibited reduced bladder blood flow relative to the sham group (P < .01); however, this measure improved in the Lig + Ana group (P < .01). CONCLUSIONS: Ana administration improved ICIs and bladder blood flow after acute bladder ischemia through a GLP-1 receptor-independent signaling pathway, without altering the blood glucose levels. Therefore, Ana dosing might be useful to prevent ischemia-induced bladder dysfunctions.


Asunto(s)
Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Hemodinámica/efectos de los fármacos , Arteria Ilíaca , Pirimidinas/uso terapéutico , Enfermedades de la Vejiga Urinaria/tratamiento farmacológico , Animales , Glucemia/metabolismo , Dieta , Dipeptidil Peptidasa 4/sangre , Femenino , Receptor del Péptido 1 Similar al Glucagón/antagonistas & inhibidores , Isquemia , Ligadura , Liraglutida/uso terapéutico , Ratas , Ratas Wistar , Enfermedades de la Vejiga Urinaria/fisiopatología
15.
Pathol Int ; 70(11): 835-843, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-32783311

RESUMEN

Encapsulated papillary carcinoma (EPC), a rare variant of papillary carcinoma of the breast, is regarded as a transition form between carcinoma in situ and invasive carcinoma. Here, we tried to identify differences in immunohistochemical phenotype between 10 EPCs with invasive properties (EPC with invasion) and 17 non-invasive EPCs (EPC). We immunohistochemically assessed the expression of hormone receptors, matrix metalloproteinase (MMP) 2 and MMP9, vascular endothelial growth factor (VEGF), CD31, and D2-40, markers of tumor-associated macrophages (CD163, CD206), Ki-67 and stem cell markers (CD44 and CD24). The frequency of MMP9-positive cases and the number of tumor-associated macrophages infiltrating into the fibrous capsule were significantly higher in EPC with invasion than in EPC. The expression of the standard form of CD44 (CD44s) was significantly stronger in EPC with invasion than in EPC (P = 0.0036) and was correlated with MMP2 expression and M2-like macrophage infiltration. A multivariate logistic model analysis showed that CD44s expression in tumor cell and infiltration of CD163 positive macrophage in EPC capsule showed an independent odds ratio for invasion of EPC. Thus, CD44s may be a potential marker predicting invasive potential of EPC and could play an important role in progression to the invasive phase of EPC.


Asunto(s)
Biomarcadores de Tumor/análisis , Neoplasias de la Mama/metabolismo , Mama/patología , Carcinoma Papilar/patología , Receptores de Hialuranos/metabolismo , Anciano , Anciano de 80 o más Años , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Mama/metabolismo , Carcinoma in Situ/metabolismo , Carcinoma in Situ/patología , Carcinoma Papilar/diagnóstico , Femenino , Humanos , Inmunohistoquímica/métodos , Persona de Mediana Edad , Receptores de Superficie Celular/metabolismo
16.
Part Fibre Toxicol ; 17(1): 48, 2020 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-33054855

RESUMEN

BACKGROUND: Multi-walled carbon nanotubes can be divided into two general subtypes: tangled and straight. MWCNT-N (60 nm in diameter) and MWCNT-7 (80-90 nm in diameter) are straight-type MWCNTs, and similarly to asbestos, both are carcinogenic to the lung and pleura when administered to rats via the airway. Injection of straight-type MWCNTs into the peritoneal cavity also induces the development of mesothelioma, however, injection of tangled-type MWCNTs into the peritoneal cavity does not induce carcinogenesis. To investigate these effects in the lung we conducted a 2-year comparative study of the potential carcinogenicities of a straight-type MWCNT, MWCNT-A (approximately 150 nm in diameter), and a tangled-type MWCNT, MWCNT-B (7.4 nm in diameter) after administration into the rat lung. Crocidolite asbestos was used as the reference material, and rats administered vehicle were used as the controls. Test materials were administered by intra-Tracheal Intra-Pulmonary Spraying (TIPS) once a week over a 7 week period (8 administrations from day 1 to day 50), followed by a 2-year observation period without further treatment. Rats were administered total doses of 0.5 or 1.0 mg MWCNT-A and MWCNT-B or 1.0 mg asbestos. RESULTS: There was no difference in survival between any of the groups. The rats administered MWCNT-A or asbestos did not have a significant increase in bronchiolo-alveolar hyperplasia or tumors in the lung. However, the rats administered MWCNT-B did have significantly elevated incidences of bronchiolo-alveolar hyperplasia and tumors in the lung: the incidence of bronchiolo-alveolar hyperplasia was 0/20, 6/20, and 9/20 in the vehicle, 0.5 mg MWCNT-B, and 1.0 mg MWCNT-B groups, respectively, and the incidence of adenoma and adenocarcinoma combined was 1/19, 5/20, and 7/20 in the vehicle, 0.5 mg MWCNT-B, and 1.0 mg MWCNT-B groups, respectively. Malignant pleural mesothelioma was not induced in any of the groups. CONCLUSIONS: The results of this initial study indicate that tangled-type MWCNT-B is carcinogenic to the rat lung when administered via the airway, and that straight-type MWCNT-A did not have higher carcinogenic potential in the rat lung than tangled-type MWCNT-B.


Asunto(s)
Contaminantes Atmosféricos/toxicidad , Nanotubos de Carbono/toxicidad , Animales , Asbesto Crocidolita , Pruebas de Carcinogenicidad , Exposición por Inhalación , Pulmón , Neoplasias Pulmonares , Mesotelioma , Ratas , Tráquea/efectos de los fármacos
17.
Arch Toxicol ; 94(12): 4085-4097, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-32833043

RESUMEN

Non-alcoholic steatohepatitis (NASH) is a recognized risk factor for liver fibrosis and malignancies, and is associated with features of metabolic syndrome, such as obesity and insulin resistance (IR). We previously demonstrated that the disturbance of connexin 32 (Cx32), a gap junctional protein of hepatocytes, exacerbated NASH in Cx32 dominant-negative transgenic (Cx32ΔTg) rats fed methionine choline-deficient diet (MCDD). MCDD is well-established means of inducing NASH in rodents; however, the Cx32ΔTg-MCDD NASH model does not reproduce obesity and IR. In this study, we aimed to establish an improved NASH model. Eight-week-old male Cx32ΔTg and wild-type (Wt) rats received a high-fat diet (HFD) with dimethylnitrosamine (DMN) for 12 weeks. The HFD with DMN led to gains in body, liver, and visceral fat weights in both genotypes. IR was significantly greater in Cx32ΔTg than in Wt rats. Elevation of serum hepatic enzymes (AST, ALT), inflammatory cytokine expressions (Tnfα, Il-6, Tgf-ß1, Il-1ß, Timp2, and Col1a1), steatohepatitis, and fibrosis were significantly greater in Cx32ΔTg as compared with Wt rats. Regarding carcinogenesis, the number and area of glutathione S-transferase placental form (GST-P)-positive preneoplastic hepatic foci were significantly increased in Cx32ΔTg versus Wt rats. Moreover, activation of NF-κB and JNK contributed to the progression of NASH in Cx32ΔTg rats. These results suggest that Cx32 dysfunction promoted the progression of NASH, metabolic syndrome, and carcinogenesis. Therefore, the novel Cx32ΔTg-HFD-DMN NASH model may be a rapid and useful tool for evaluating the progression of NASH.


Asunto(s)
Transformación Celular Neoplásica/metabolismo , Conexinas/metabolismo , Cirrosis Hepática Experimental/etiología , Neoplasias Hepáticas Experimentales/etiología , Hígado/metabolismo , Enfermedad del Hígado Graso no Alcohólico/etiología , Animales , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Conexinas/genética , Citocinas/metabolismo , Dieta Alta en Grasa , Dimetilnitrosamina , Progresión de la Enfermedad , Mediadores de Inflamación/metabolismo , Resistencia a la Insulina , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Hígado/patología , Cirrosis Hepática Experimental/genética , Cirrosis Hepática Experimental/metabolismo , Cirrosis Hepática Experimental/patología , Neoplasias Hepáticas Experimentales/genética , Neoplasias Hepáticas Experimentales/metabolismo , Neoplasias Hepáticas Experimentales/patología , Masculino , FN-kappa B/metabolismo , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Ratas Transgénicas , Transducción de Señal , Proteína beta1 de Unión Comunicante
18.
Molecules ; 25(12)2020 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-32545675

RESUMEN

Curcumin (Cur) exhibits biological activities that support its candidacy for cancer treatment. However, there are limitations to its pharmacological effects, such as poor solubility and bioavailability. Notably, the use of Cur analogs has potential for addressing these limitations. Dehydrozingerone (DZG) is a representative of the half-chemical structure of Cur, and many reports have indicated that it is anticancer in vitro. We, therefore, have hypothesized that DZG could inhibit prostate cancer progression both in vitro and in vivo. Results revealed that DZG decreased cell proliferation of rat castration-resistant prostate cancer, PLS10 cells, via induction of the cell cycle arrest in the G1 phase in vitro. In the PLS10 xenograft model, DZG significantly decreased the growth of subcutaneous tumors when compared to the control via the inhibition of cell proliferation and angiogenesis. To prove that DZG could improve the limitations of Cur, an in vivo pharmacokinetic was determined. DZG was detected in the serum at higher concentrations and remained up to 3 h after intraperitoneal injections, which was longer than Cur. DZG also showed superior in vivo tissue distribution than Cur. The results suggest that DZG could be a candidate of the Cur analog that can potentially exert anticancer capabilities in vivo and thereby improve its bioavailability.


Asunto(s)
Neoplasias de la Próstata/tratamiento farmacológico , Estirenos/farmacología , Animales , Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Disponibilidad Biológica , Técnicas de Cultivo de Célula/métodos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Curcumina/análogos & derivados , Curcumina/farmacología , Portadores de Fármacos/química , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Nanopartículas/química , Tamaño de la Partícula , Neoplasias de la Próstata/metabolismo , Ratas , Estirenos/metabolismo
19.
J Toxicol Pathol ; 33(4): 279-285, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-33239845

RESUMEN

Phosphorylation of histone H2AX at serine 139 (γ-H2AX) is known to be induced by direct DNA damage or cellular metabolic imbalances and malfunctions. Previous studies have reported that γ-H2AX is a useful biomarker for early detection of genotoxic bladder carcinogens in rats. The purpose of the present study was to determine the role of γ-H2AX as a biomarker for detection of non-genotoxic bladder carcinogens in rats. Six-week-old male F344 rats were treated with 15 different chemicals for 4 weeks. Immunohistochemical analyses revealed that all three genotoxic bladder carcinogens and six out of seven non-genotoxic bladder carcinogens significantly increased γ-H2AX formation in the bladder urothelium of rats. In addition, four out of five rat bladder noncarcinogens did not increase γ-H2AX formation in the bladder urothelium regardless of genotoxicity. These results suggest that γ-H2AX is a useful biomarker for detection of both genotoxic and non-genotoxic bladder carcinogens in rats.

20.
Cancer Sci ; 110(2): 596-607, 2019 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-30499149

RESUMEN

Many prostate cancer patients develop resistance to treatment called castration-resistant prostate cancer (CRPC) which is the major cause of recurrence and death. In the present study, four cyclohexanone curcumin analogs were synthesized. Additionally, their anticancer progression activity on CRPC cell lines, PC3 and PLS10 cells, was examined. We first determined their anti-metastasis properties and found that 2,6-bis-(4-hydroxy-3-methoxy-benzylidene)-cyclohexanone (2A) and 2,6-bis-(3,4-dihydroxy-benzylidene)-cyclohexanone (2F) showed higher anti-invasion properties against CRPC cells than curcumin. Analog 2A inhibited both MMP-2 and MMP-9 secretions and activities, whereas analog 2F reduced only MMP activities. These findings suggest that the compounds may inhibit CRPC cell metastasis by decreased extracellular matrix degradation. Analog 2A, the most potent analog, was then subjected to an in vivo study. Similar to curcumin, analog 2A was detectable in the serum of mice at 30 and 60 minutes after i.p. injections. Analog 2A and curcumin (30 mg/kg bodyweight) showed a similar ability to reduce tumor area in lungs of mice that were i.v. injected with PLS10 cells. Additionally, analog 2A showed superior growth inhibitory effect on PLS10 cells than that of curcumin both in vitro and in vivo. The compound inhibited PLS10 cells growth by induction of G1 phase arrest and apoptosis in vitro. Interestingly, analog 2A significantly decreased tumor growth with downregulation of cell proliferation and angiogenesis in PLS10-bearing mice. Taken together, we could summarize that analog 2A showed promising activities in inhibiting CRPC progression both in vitro and in vivo.


Asunto(s)
Curcumina/farmacología , Ciclohexanonas/farmacología , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Progresión de la Enfermedad , Resistencia a Antineoplásicos/efectos de los fármacos , Humanos , Masculino , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/metabolismo , Células PC-3 , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto/métodos
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