Combined rapamycin-octreotide treatment has a stronger antiproliferative effect on non-functioning pituitary tumor cells compared with each drug alone. The mechanism of the combined treatment action was studied in AtT-20 pituitary tumor cells. Rapamycin is known to induce cell cycle arrest at the G1/S transition point. The entry of eukaryotic cells into the cell cycle is controlled primarily by the activation of cyclin-dependent kinases (CDK4/CDK6 and CDK2) by their respective cyclin partners (cyclin D1, D2, D3, and E). D-type cyclins form catalytically active kinase complexes with CDK4 and CDK6 which phosphorylate and inactivate the tumour suppressor Rb. Cyclin E forms complexes with CDK2 completing the phosphorylation and inactivation of Rb and leading to irreversible entry into the S-phase of the cell cycle. Cyclin D/CDK4 and cyclin D/CDK6 activity is inhibited by members of the INK4 CDK inhibitor family (e.g. p16/INK4A), while cyclin E/CDK2 is inhibited by p21/Cip1 and p27/Kip1. Rapamycin treatment decreased cyclin D1/D3 and CDK4/6 levels, while octreotide had no effect. Addition of octreotide to rapamycin did not potentiate rapamycins effect. In contrast, both rapamycin and octreotide increased p27/Kip1 and decreased Cdk2 and cyclin E levels and their combination The two drugs together potentiated their action, providing a mechanism for the better antiproliferative effect of the combined compared to the single treatment. It is important to note that p27/kip1 is a tumour suppressor gene that plays a significant role in pituitary tumorigenesis, since p27 knock-out mice present with pituitary tumours and p27/Kip1 protein is dysregulated in many human pituitary adenoma types. Therefore, the superior effect of the combined treatment, compared to each drug alone, on p27/Kip1 expression may in part explain its better antiproliferative action in pituitary tumor cells.
03 - 07 May 2008
European Society of Endocrinology