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In vivo effects of rosiglitazone in a human neuroblastoma xenograft.

Cellai I, Petrangolini G, Tortoreto M, Pratesi G, Luciani P, Deledda C, Benvenuti S, Ricordati C, Gelmini S, Ceni E, Galli A, Balzi M, Faraoni P, Serio M, Peri A - Br. J. Cancer (2010)

Bottom Line: We have previously demonstrated that the PPARgamma agonist rosiglitazone (RGZ) exerts strong anti-tumoural effects in the human NB cell line, SK-N-AS.The aim of this study was to evaluate whether RGZ maintains its anti-tumoural effects against SK-N-AS NB cells in vivo.To our knowledge, this is the first demonstration that RGZ effectively inhibits tumour growth in a human NB xenograft and our results suggest that PPARgamma agonists may have a role in anti-tumoural strategies against NB.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Physiopathology, Center for Research, University of Florence, Italy.

ABSTRACT

Background: Neuroblastoma (NB) is the most common extra-cranial solid tumour in infants. Unfortunately, most children present with advanced disease and have a poor prognosis. There is in vitro evidence that the peroxisome proliferator-activated receptor gamma (PPARgamma) might be a target for pharmacological intervention in NB. We have previously demonstrated that the PPARgamma agonist rosiglitazone (RGZ) exerts strong anti-tumoural effects in the human NB cell line, SK-N-AS. The aim of this study was to evaluate whether RGZ maintains its anti-tumoural effects against SK-N-AS NB cells in vivo.

Methods and results: For this purpose, tumour cells were subcutaneously implanted in nude mice, and RGZ (150 mg kg(-1)) was administered by gavage daily for 4 weeks. At the end of treatment, a significant tumour weight inhibition (70%) was observed in RGZ-treated mice compared with control mice. The inhibition of tumour growth was supported by a strong anti-angiogenic activity, as assessed by CD-31 immunostaining in tumour samples. The number of apoptotic cells, as determined by cleaved caspase-3 immunostaining, seemed lower in RGZ-treated animals at the end of the treatment period than in control mice, likely because of the large tumour size observed in the latter group.

Conclusions: To our knowledge, this is the first demonstration that RGZ effectively inhibits tumour growth in a human NB xenograft and our results suggest that PPARgamma agonists may have a role in anti-tumoural strategies against NB.

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Related in: MedlinePlus

Relationship between tumour weight and cleaved caspase-3 immunopositive cells in SK-N-AS neuroblastoma xenografts. Black squares indicate solvent-treated tumours. R=0.835, P<0.05, by Spearman's rank correlation test.
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fig4: Relationship between tumour weight and cleaved caspase-3 immunopositive cells in SK-N-AS neuroblastoma xenografts. Black squares indicate solvent-treated tumours. R=0.835, P<0.05, by Spearman's rank correlation test.

Mentions: With regard to apoptosis, at short-time observation (2 weeks), that is, in the presence of small-sized tumours, a low number of apoptotic cells was present, but in mice treated with RGZ, the number of cleaved caspase-3 immunopositive cells was higher than in controls, although the difference was not statistically significant (P=0.12) (Table 1 and Figure 3A). At such a time, necrosis was virtually absent in RGZ-treated tumours and rare and very limited necrotic areas were present in control tumours. A different pattern was observed in samples from mice killed after 4 weeks of treatment, in which, in large-sized control tumours (mean TW>2 g), large necrotic areas and a high number of apoptotic cells were observed. At such a time, in RGZ-treated tumours, the number of caspase-3 immunopositive cells was significantly lower (P<0.05) and necrotic areas were less extended than in solvent-treated tumours (Table 1 and Figure 3B). Figure 4 shows that, in control mice, a linear relation (R=0.835, P<0.05, by Spearman's rank correlation test) between positive staining for cleaved caspase-3 and tumour size was found. These results indicate that at the 2-week observation time, RGZ treatment increases the apoptotic index, whereas at 4 weeks, necrosis and apoptotic index are likely to be related to tumour size. Nevertheless, if we compare the rate of apoptosis in tumour samples of the same size from solvent-treated or RGZ-treated mice, we can observe that when in both groups the TW reached 670 g (i.e., the mean weight of tumours in RGZ-treated mice at the end of treatment, approximately corresponding to the weight of tumours in control mice after 2 weeks), the mean percentage of apoptotic cells was 10% in control mice, whereas it reached 30% in RGZ-treated mice (Figures 2 and 3).


In vivo effects of rosiglitazone in a human neuroblastoma xenograft.

Cellai I, Petrangolini G, Tortoreto M, Pratesi G, Luciani P, Deledda C, Benvenuti S, Ricordati C, Gelmini S, Ceni E, Galli A, Balzi M, Faraoni P, Serio M, Peri A - Br. J. Cancer (2010)

Relationship between tumour weight and cleaved caspase-3 immunopositive cells in SK-N-AS neuroblastoma xenografts. Black squares indicate solvent-treated tumours. R=0.835, P<0.05, by Spearman's rank correlation test.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2837558&req=5

fig4: Relationship between tumour weight and cleaved caspase-3 immunopositive cells in SK-N-AS neuroblastoma xenografts. Black squares indicate solvent-treated tumours. R=0.835, P<0.05, by Spearman's rank correlation test.
Mentions: With regard to apoptosis, at short-time observation (2 weeks), that is, in the presence of small-sized tumours, a low number of apoptotic cells was present, but in mice treated with RGZ, the number of cleaved caspase-3 immunopositive cells was higher than in controls, although the difference was not statistically significant (P=0.12) (Table 1 and Figure 3A). At such a time, necrosis was virtually absent in RGZ-treated tumours and rare and very limited necrotic areas were present in control tumours. A different pattern was observed in samples from mice killed after 4 weeks of treatment, in which, in large-sized control tumours (mean TW>2 g), large necrotic areas and a high number of apoptotic cells were observed. At such a time, in RGZ-treated tumours, the number of caspase-3 immunopositive cells was significantly lower (P<0.05) and necrotic areas were less extended than in solvent-treated tumours (Table 1 and Figure 3B). Figure 4 shows that, in control mice, a linear relation (R=0.835, P<0.05, by Spearman's rank correlation test) between positive staining for cleaved caspase-3 and tumour size was found. These results indicate that at the 2-week observation time, RGZ treatment increases the apoptotic index, whereas at 4 weeks, necrosis and apoptotic index are likely to be related to tumour size. Nevertheless, if we compare the rate of apoptosis in tumour samples of the same size from solvent-treated or RGZ-treated mice, we can observe that when in both groups the TW reached 670 g (i.e., the mean weight of tumours in RGZ-treated mice at the end of treatment, approximately corresponding to the weight of tumours in control mice after 2 weeks), the mean percentage of apoptotic cells was 10% in control mice, whereas it reached 30% in RGZ-treated mice (Figures 2 and 3).

Bottom Line: We have previously demonstrated that the PPARgamma agonist rosiglitazone (RGZ) exerts strong anti-tumoural effects in the human NB cell line, SK-N-AS.The aim of this study was to evaluate whether RGZ maintains its anti-tumoural effects against SK-N-AS NB cells in vivo.To our knowledge, this is the first demonstration that RGZ effectively inhibits tumour growth in a human NB xenograft and our results suggest that PPARgamma agonists may have a role in anti-tumoural strategies against NB.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Physiopathology, Center for Research, University of Florence, Italy.

ABSTRACT

Background: Neuroblastoma (NB) is the most common extra-cranial solid tumour in infants. Unfortunately, most children present with advanced disease and have a poor prognosis. There is in vitro evidence that the peroxisome proliferator-activated receptor gamma (PPARgamma) might be a target for pharmacological intervention in NB. We have previously demonstrated that the PPARgamma agonist rosiglitazone (RGZ) exerts strong anti-tumoural effects in the human NB cell line, SK-N-AS. The aim of this study was to evaluate whether RGZ maintains its anti-tumoural effects against SK-N-AS NB cells in vivo.

Methods and results: For this purpose, tumour cells were subcutaneously implanted in nude mice, and RGZ (150 mg kg(-1)) was administered by gavage daily for 4 weeks. At the end of treatment, a significant tumour weight inhibition (70%) was observed in RGZ-treated mice compared with control mice. The inhibition of tumour growth was supported by a strong anti-angiogenic activity, as assessed by CD-31 immunostaining in tumour samples. The number of apoptotic cells, as determined by cleaved caspase-3 immunostaining, seemed lower in RGZ-treated animals at the end of the treatment period than in control mice, likely because of the large tumour size observed in the latter group.

Conclusions: To our knowledge, this is the first demonstration that RGZ effectively inhibits tumour growth in a human NB xenograft and our results suggest that PPARgamma agonists may have a role in anti-tumoural strategies against NB.

Show MeSH
Related in: MedlinePlus