ECE2014 Poster Presentations Adrenal Medulla (8 abstracts)
Expression of IGF/mTOR pathway components in human pheochromocytomas and in vitro inhibition of PC12 rat pheochromocytoma cell growth by mTOR inhibitors alone and in combination with the dual IGFI-R/INS-R antagonist OSI-906
Maria Cristina De Martino 1, , Richard A. Feelders 2 , Fadime Dogan 2 , Peter M. van Koetsveld 2 , Ronald R. De Krijger 3 , Joseph A M J L Janssen 2 , Diana Sprij-Mooij 2 , Steven W. J. Lamberts 2 , Wouter W de Herder 2 , Annamaria Colao 2 , Rosario Pivonello 2 & Leo J Hofland 2
1Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II, Naples, Italy; 2Division of Endocrinology, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands; 3Department of Pathology, Erasmus MC, Rotterdam, The Netherlands.
The mTOR and IGF pathways have been suggested to play a role in the pathogenesis of pheochromocytomas (PCC). mTOR inhibitors, as sirolimus (S) and everolimus (E), as well as IGF1R antagonists could be a potential novel treatment for malignant PPC.
The aim of this study was to evaluate the expression of the main components of the IGF/mTOR pathway in human PCC and to investigate the effects of the mTOR inhibitors S and E and of the IGF1R/insulin receptor (IR) blocker OSI-906, alone or in combination in a rat PCC cell model.
mRNA expression of IGF1, IGF2, IGF1-receptor (IGFR), IR subtype A and B, IGF2R, IGF-binding-proteins (BP) 1, 2, 3 and 6, mTOR, 4EBP1 and p70S6K was evaluated in 24 human PCC by quantitative-PCR. In PC12 cells, the dose- and time-dependent effect of S, E and OSI-906 and the effect of combined selected doses of S and OSI-906 on cell growth and apoptosis were tested by measurement of total DNA content and DNA fragmentation assay respectively.
In human PCC a high expression of IGF2 mRNA and an increased IRA/IRB ratio was found. No correlations between the expression of the main components of the IGF/mTOR pathway and the main clinical characteristics (age of diagnosis, the longest tumor diameter, malignancy and genetic syndrome) were observed. S, E and OSI-906 were able to suppress PC12 proliferation in a dose and time-dependent manner. After a 6 day treatment maximal inhibitory effects of S, E and OSI-906 on PC12 cell proliferation were 52, 43, and 69% respectively. S was slightly but significantly more potent than E. OSI-906 stimulated cell apoptosis (1249%). Combined treatment of S with OSI-906 had additive antiproliferative effects (25% of maximal additive effect at the combined doses tested; P<0.001).
The results of the current study suggest the use of OSI-906, alone or in combination with mTOR inhibitors, as a potential novel treatment for patients with PCC.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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