Pasireotide and octreotide antiproliferative effects and sst2 trafficking in human pancreatic neuroendocrine tumor cultures.

Abstract

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) raise difficult therapeutic problems despite the emergence of targeted therapies. Somatostatin analogs (SSA) remain pivotal therapeutic drugs. However, the tachyphylaxis and the limited antitumoral effects observed with the classical somatostatin 2 (sst2) agonists (octreotide and lanreotide) led to the development of new SSA, such as the pan sst receptor agonist pasireotide. Our aim was to compare the effects of pasireotide and octreotide on cell survival, chromogranin A (CgA) secretion, and sst2 phosphorylation/trafficking in pancreatic NET (pNET) primary cells from 15 tumors. We established and characterized the primary cultures of human pancreatic tumors (pNETs) as powerful preclinical models for understanding the biological effects of SSA. At clinically relevant concentrations (1-10 nM), pasireotide was at least as efficient as octreotide in inhibiting CgA secretion and cell viability through caspase-dependent apoptosis during short treatments, irrespective of the expression levels of the different sst receptors or the WHO grade of the parental tumor. Interestingly, unlike octreotide, which induces a rapid and persistent partial internalization of sst2 associated with its phosphorylation on Ser341/343, pasireotide did not phosphorylate sst2 and induced a rapid and transient internalization of the receptor followed by a persistent recycling at the cell surface. These results provide the first evidence, to our knowledge, of striking differences in the dynamics of sst2 trafficking in pNET cells treated with the two SSAs, but with similar efficiency in the control of CgA secretion and cell viability.

• Authors: Amira Mohamed, Marie-Pierre Blanchard, Manuela Albertelli, Federica Barbieri, Thierry Brue, Patricia Niccoli, Jean-Robert Delpero, Genevieve Monges, Stephane Garcia, Diego Ferone, Tullio Florio, Alain Enjalbert, Vincent Moutardier, Agnes Schonbrunn, Corinne Gerard, Anne Barlier, Alexandru Saveanu
• Journal: Endocrine-related cancer (Endocr Relat Cancer) Vol. 21 Issue 5 Pg. 691-704 (Oct 2014) ISSN: 1479-6821 [Electronic] England
• PMID: 25012983 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 Society for Endocrinology.

Chemical References

• Antineoplastic Agents, Hormonal
• Chromogranin A
• Receptors, Somatostatin
• Somatostatin
• pasireotide
• somatostatin receptor 2
• Cyclic AMP
• Caspase 3
• Caspase 7
• Octreotide

Topics

• Adult
• Aged
• Antineoplastic Agents, Hormonal (pharmacology)
• Apoptosis (drug effects)
• Caspase 3 (metabolism)
• Caspase 7 (metabolism)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Chromogranin A (metabolism)
• Cyclic AMP (metabolism)
• DNA Fragmentation
• Female
• Humans
• Intestinal Neoplasms (metabolism)
• Male
• Middle Aged
• Neuroendocrine Tumors (metabolism)
• Octreotide (pharmacology)
• Pancreatic Neoplasms (metabolism)
• Receptors, Somatostatin (metabolism)
• Somatostatin (analogs & derivatives, pharmacology)
• Stomach Neoplasms (metabolism)
• Tumor Cells, Cultured