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Mol Cancer Ther. 2016 Jun;15(6):1261-70. doi: 10.1158/1535-7163.MCT-15-0891. Epub 2016 Mar 16.

Differential Effects of PI3K and Dual PI3K/mTOR Inhibition in Rat Prolactin-Secreting Pituitary Tumors.

Author information

1
INSERM U1052, CNRS UMR5286, Cancer Research Center of Lyon, Lyon, France. Université Lyon 1, Lyon, France.
2
Centre de Biologie Est, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France. gerald.raverot@chu-lyon.fr.
3
INSERM U1052, CNRS UMR5286, Cancer Research Center of Lyon, Lyon, France.
4
Max-Planck Institute for Psychiatry, Munich, Germany.
5
INSERM U1052, CNRS UMR5286, Cancer Research Center of Lyon, Lyon, France. Université Lyon 1, Lyon, France. Service de Neurochirurgie, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France.
6
Université Lyon 1, Lyon, France. Centre de Pathologie Est, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France. INSERM U1028, CNRS UMR5292, Lyon Neuroscience Research Center, Neuro-oncology and Neuro-inflammation Team, Lyon, France.
7
Université Lyon 1, Lyon, France. INSERM U1028, CNRS UMR5292, Lyon Neuroscience Research Center, Neuro-oncology and Neuro-inflammation Team, Lyon, France.
8
INSERM U1052, CNRS UMR5286, Cancer Research Center of Lyon, Lyon, France. Université Lyon 1, Lyon, France. Fédération d'Endocrinologie, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France.

Abstract

Aggressive pituitary tumors are rare but difficult to manage, as there is no effective chemotherapy to restrict their growth and cause their shrinkage. Within these tumors, growth-promoting cascades, like the PI3K/mTOR pathway, appear to be activated. We tested the efficacy of two inhibitors of this pathway, NVP-BKM120 (Buparlisib; pan-PI3K) and NVP-BEZ235 (dual PI3K/mTOR), both in vitro on immortalized pituitary tumor cells (GH3) and on primary cell cultures of human pituitary tumors and in vivo on a rat model of prolactin (PRL) tumors (SMtTW3). In vitro, NVP-BEZ235 had a potent apoptotic and cytostatic effect that was characterized by decreased cyclin D/E and Cdk4/2 protein levels and subsequent accumulation of cells in G1 In vivo, the effect was transient, with a decrease in mitotic index and increase in apoptosis; long-term treatment had no significant inhibitory effect on tumor growth. In contrast, while NVP-BKM120 had little effect in vitro, it dramatically limited tumor growth in vivo Increased Akt phosphorylation observed only in the NVP-BEZ235-treated tumors may explain the differential response to the two inhibitors. Primary cell cultures of human PRL pituitary tumors responded to NVP-BEZ235 with reduced cell viability and decreased hormone secretion, whereas NVP-BKM120 had little effect. Altogether, these results show a potential for PI3K inhibitors in the management of aggressive pituitary tumors. Mol Cancer Ther; 15(6); 1261-70.

PMID:
26983879
DOI:
10.1158/1535-7163.MCT-15-0891
[Indexed for MEDLINE]
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