Cell specific interaction of pasireotide: review of preclinical studies in somatotroph and corticotroph pituitary cells.

BACKGROUND

Pasireotide is a second-generation somatostatin (SRIF) receptor ligand (SRL), approved for medical treatment of acromegaly and Cushing's disease (CD). The molecule is a stable cyclohexapeptide synthetized based on SRIF structure. Differently from first-generation SRLs (e.g. octreotide), preferentially binding somatostatin receptor (SST) subtype 2 (SST), pasireotide has high affinity for multiple SSTs (SST > SST > SST > SST). Interestingly, early preclinical studies demonstrated that pasireotide shows distinct functional properties compared to SRIF and first-generation SRLs when binding SSTs.

METHODS

We aimed to highlight the differential receptor-targeted action of pasireotide in the treatment of somatotroph and corticotroph adenomas, throughout the critical revision of preclinical studies carried out on acromegaly and CD models.

RESULTS

Different authors demonstrated that the antisecretory effect of pasireotide in somatotroph adenoma cell cultures is comparable to that of the SST-preferential agonist octreotide. Some reports even show a direct correlation between SST mRNA expression and GH reduction after pasireotide treatment, thus laying for a predominant role of SST in driving pasireotide efficacy in somatotropinomas in vitro. On the other hand, the inhibitory effect of pasireotide on ACTH secretion in corticotropinoma cells seems to be mainly mediated by SST. Indeed, most reports show a higher potency and efficacy of pasireotide compared to SST preferential agonists, while functional studies confirm the pivotal role of SST targeting in corticotroph cells.

CONCLUSIONS

The analysis of preclinical studies carried out in somatotroph and corticoph adenomas points out that pasireotide shows a cell-specific activity, exerting its biological effects via different SSTs in the different adenoma histotypes.