Papers by Denise Belgorosky
The Journal of urology, 2012
We evaluated the effects of combined PPARg agonist with bacillus Calmette-Guérin in bladder cance... more We evaluated the effects of combined PPARg agonist with bacillus Calmette-Guérin in bladder cancer growth in vitro and in vivo, focusing on the tissue remodeling mechanisms induced by bacillus Calmette-Guérin. PPARs are a superfamily of nuclear receptors that are transcription factors activated by ligands. Activation of PPARg, the γ subtype, causes proliferation inhibition or differentiation of tumor cells. Previously, we reported that the inhibition of murine bladder tumor growth induced by bacillus Calmette-Guérin, which is the standard treatment for patients with nonmuscle invasive, high grade bladder cancer, increased PPARg expression in vitro and in vivo. In vitro the cell growth inhibition induced by bacillus Calmette-Guérin was enhanced by the PPARg agonist 15-d-PGJ2, raising the possibility that PPARg activation may be a therapeutic modality for this disease. In MB49 cells bacillus Calmette-Guérin and 15-d-PGJ2 induced PPARg expression, nuclear translocation and transcriptio...
Reproductive BioMedicine Online, 2010
received her PhD from the University of Buenos Aires, Argentina. Her early research interests wer... more received her PhD from the University of Buenos Aires, Argentina. Her early research interests were in studying the mechanisms involved in corpus luteum regression. As a post-doctoral researcher she began to work on the mechanisms involved in the outcome and development of polycystic ovary syndrome. In that context, she developed rodent models to study this pathology during the prepuberal stage and in early pregnancy. She is currently a researcher for the Abstract This study aimed to investigate how hyperandrogenism affects early folliculogenesis. Hyperandrogenism was induced in prepuberal female BALB/c mice by daily s.c. injection of dehydroepiandrosterone (60 mg/kg body weight in 0.1 ml sesame oil) for 10 consecutive days. Although hyperandrogenism increased the growth rate of primary follicles, it also increased ovarian oxidative stress (evaluated by the increase in lipid peroxidation, the decrease in superoxide dismutase activity and the fact that glutathione content was not modified). By using the annexin V/cytometry assay it was found that the excess of androgens decreased viable ovarian cells and increased early apoptotic ones. The increased lipid peroxidation induced enhanced ovarian prostaglandin E production. In addition, hyperandrogenism increased the number of T lymphocytes that infiltrate ovarian tissue and modified their phenotype (decreased CD4+ or helper and increased the suppressor/cytotoxic CD8+). The excess of androgens decreased the ovarian expression of the long isoform of leptin receptor (Ob-Rb, the only isoform expressed in the ovarian tissue) when compared with controls. All these alterations increased serum concentrations of oestradiol, a pro-apoptotic agent. It is concluded that the excess of androgens impairs early follicular development by modulating some endocrine and immune parameters that are either directly or indirectly related to follicular atresia. RBMOnline
The Journal of Urology, 2015
Bacillus Calmette-Guerin (BCG) is the standard treatment for patients with non-muscle invasive hi... more Bacillus Calmette-Guerin (BCG) is the standard treatment for patients with non-muscle invasive high histological grade bladder cancer (BC). Previously, we have demonstrated that BCG induces murine BC MB49 cell death both in vitro and in vivo, generating tissue remodeling, which involves the release of fibroblast growth factor 2 (FGF-2). To study the effect of BCG treatment in FGF-2 and fibroblast growth factor receptors (FGFRs) expression in BC. In vitro, FGF-2 increased MB49 cell proliferation, but was not able to reverse BCG-induced cell death. An increased expression of FGF-2 was detected after BCG treatment. Moreover, MB49 cells expressed high FGFR3 levels, which decreased after BCG treatment. Similar results were observed in human T24 BC cells. In vivo, MB49 tumors expressed higher FGFR3 levels than normal urothelium. Tumor FGFR3 decreased after treatment and correlates with tumor growth inhibition in response to BCG. In a pilot bioassay using human bladder tumors (n=11) treated ex vivo with BCG, we found a sub-group of patients (41%) where FGFR3 was reduced after treatment. Based on BC murine model results, we can infer that the down-regulation of FGFR3 is a predictive marker of good response for BCG therapy. The decrease of FGFR3 in response to BCG occurs not only in the murine model but also in a human BC cell line and in some patient samples. Both, the increase of patients and their follow-up are necessary to establish the predictive role of FGFR3 as a marker in human BC.
The Journal of Urology, 2012
We evaluated the role of inducible nitric oxide synthase and PPARγ as prognostic factors for blad... more We evaluated the role of inducible nitric oxide synthase and PPARγ as prognostic factors for bladder cancer. Inducible nitric oxide synthase and PPARγ were evaluated by Western blot and immunohistochemistry in a mouse bladder cancer model of nonmuscle invasive and invasive MB49-I tumor cells, and in human bladder cancer samples. Inducible nitric oxide synthase expression was negative in mouse normal urothelium and higher in invasive than in noninvasive MB49 tumors. In vitro inducible nitric oxide synthase activity, determined as nitrite, was higher in MB49-I than in MB49 cells (p <0.001). In human samples expression was also associated with tumor invasion. Nuclear PPARγ expression was negative in normal mouse urothelium but higher in nonmuscle invasive MB49 than in MB49-I tumors. Similarly in human tumors low PPARγ was associated with poor prognosis factors, such as high histological grade (p = 0.0160) and invasion status (p = 0.0352). A positive correlation was noted between inducible nitric oxide synthase and PPARγ in low histological grade and nonmuscle invasive tumors (Pearson correlation index 0.6368, p = 0.0351, 0.4438 and 0.0168, respectively). As determined by gene reporter assay, PPARγ activity was induced by nitric oxide only in nonmuscle invasive MB49 cells (p <0.001). Results suggest that increased PPARγ controls inducible nitric oxide synthase expression at early tumor stages. However, regulation is lost at advanced tumor stages, when the increase in inducible nitric oxide synthase and the decrease in PPARγ seem to be associated with bladder cancer progression.
European journal of medicinal chemistry, Jan 13, 2015
Inflammation plays a crucial role in many types of cancer and is known to be involved in their in... more Inflammation plays a crucial role in many types of cancer and is known to be involved in their initiation and promotion. As such, it is presently recognized as an important risk factor for several types of cancers such as bladder, prostate and breast cancers. The discovery of novel anti-inflammatory compounds can have a huge implication not only for the treatment of cancer but also as preventive and protective treatment modalities. We have recently identified a new compound (1) that presents interesting anti-inflammatory activity. In order to better understand its biological action, we have divided the molecule in its basic components and verified their respective contribution towards the anti-inflammatory response of the whole molecule. We have discovered that only the combination of the maleimide function together with the tert-butyloxycarbonylhydrazinamide function lead to important anti-inflammatory properties. The main derivative 1 can decrease the activating effects of INFγ or...
Molecular Human Reproduction, 2009
The present study investigated the role of the N, N 0 -dimethylbiguanide metformin (50 mg/kg body... more The present study investigated the role of the N, N 0 -dimethylbiguanide metformin (50 mg/kg body weight in 0.05 ml water, given orally with a canulla) in preventing the adverse effects generated by hyperandrogenism on uterine function. Daily injection of dehydroepiandrosterone (DHEA: 6 mg/100 g body weight in 0.1 ml oil) for 20 consecutive days induces polycystic ovaries in BALB/c mice. In this model we found that DHEA produced alterations on uterine histology closely related to the development of pre-cancerous structures concomitantly with increased incidence of uterine apoptosis. The injection of DHEA induced a pro-inflammatory status since uterine prostaglandin (PG) F2 alpha levels and cyclooxygenase 2 were increased although PGE levels were decreased. Furthermore, DHEA promoted a pro-oxidant status since it increased nitric oxide synthase (NOS) activity and decreased superoxide dismutase and catalase activities and the antioxidant metabolite glutathione levels. DHEA also regulated the percentages of CD4þ and CD8þ T lymphocyte that infiltrate uterine tissue. When metformin was administered together with DHEA uterine histology and apoptosis did not differ when compared with controls. Therefore, metformin prevented the pro-inflammatory and pro-oxidative status generated by DHEA and restores the ratios of CD4þ and CD8þ T cells to those observed in controls. We conclude that metformin is able to restore either directly or indirectly uterine function by preventing some inflammatory and oxidative alterations produced by hyperandrogenism.
Cancer Genetics, 2012
Bladder cancer is frequently associated with chromosomal abnormalities, and the complexity of kar... more Bladder cancer is frequently associated with chromosomal abnormalities, and the complexity of karyotypes increases with tumor progression. The murine model MB49 is one of the most widely studied models of bladder cancer. We developed the invasive cell line MB49-I by successive in vivo passages of MB49 primary tumors. Because little is known about the chromosomal alterations of this model, our goal was to perform cytogenetic analyses of the MB49 and MB49-I lines. The karyotypes of both lines were analyzed by G-banding and fluorescence in situ hybridization techniques. Both lines were composed of two cell subpopulations, a diploid population, which was found mainly in the MB49 line, and the tetraploid population, which was found mainly in the MB49-I line. A translocation between chromosomes 5 and 9 and an isochromosome of chromosome 19 were observed in the subpopulations of both lines. New structural abnormalities and additional chromosomal imbalances were detected in the MB49-I line. Tumor progression in the MB49/MB49-I model was associated with a selection of polyploid cells with accompanying chromosomal abnormalities. This model may be advantageous for the study of the genetic changes associated with the progression of bladder cancer.
Nitric Oxide, 2014
Bladder cancer is the second cause of death for urological tumors in man. When the tumor is nonmu... more Bladder cancer is the second cause of death for urological tumors in man. When the tumor is nonmuscle invasive, transurethral resection is curative. On the other hand, radical cystectomy is the treatment chosen for patients with invasive tumors, but still under treatment, these patients have high risk of dying, by the development of metastatic disease within 5 years. It is therefore important to identify a new therapeutic target to avoid tumor recurrences and tumor progression. Nitric oxide (NO) is an important biological messenger known to influence several types of cancers. In bladder cancer, production of NO and expression and activity of inducible NO synthase was associated to recurrence and progression. The objective of this work was to analyze if inhibition of nitric oxide production could be considered a therapeutic target for bladder tumors expressing iNOS. Using a bladder cancer murine model with different invasiveness grade we have demonstrated that NO inhibition was able to inhibit growth of bladder tumors expressing iNOS. Furthermore, invasive properties of MB49-I orthotopic growth was inhibited using NO inhibitors. This paper also shows that levels of NO in urine can be correlated with tumor size. In conclusion, inhibition of NO could be considered as a therapeutic target that prevents tumor growth and progression. Also, urine NO levels may be useful for measuring tumor growth.
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Papers by Denise Belgorosky