13, 28, 29 Activation of SSTR3 is also known to reduce proliferation and/or induce apoptosis.4 Indeed, we found that OCT and PAS Palbociclib manufacturer inhibited cAMP and cell proliferation in rat and human cystic cholangiocytes in vitro and decreased mitotic indices and increased apoptotic indices in rodent models of PLD and PKD. Moreover, the effects of PAS were consistently more potent than OCT. In line with our data, PAS has been shown by others to decrease cell proliferation and cAMP in several different cell lines to a greater extent than OCT.17, 21, 24-26 We speculate that more potent PAS effects are likely related to the following. First, we observed the reduced expression of SSTR1 and SSTR2

in cystic cholangiocytes, whereas levels of SSTR3 and SSTR5 were not affected. Second, SSTR2, SSTR3, and SSTR5 are targets of OCT and PAS, whereas Metabolism inhibitor SSTR1 is the target of PAS only. Third, the binding affinity of PAS to SSTR3 and SSTR5 is 5-fold and 39-fold, respectively, higher compared with OCT.17 OCT and PAS modulate their action both by way of direct (i.e., cell proliferation, apoptosis, and cell cycle regulation) and indirect effects. Indirect effects occur, in particular, through inhibition of secretion of IGF1 and VEGF.13, 15 Both growth factors are overexpressed in cystic cholangiocytes and have been implicated in hepatorenal cystogenesis

influencing cyst growth by both autocrine and paracrine pathways.3, 16, 18, 19 In the present study, the VEGF concentrations were not affected by either drug. OCT also had no effect on IGF1 concentration, whereas PAS reduced it. This result 上海皓元医药股份有限公司 is consistent with previous data and suggests that the observed greater action of PAS on hepatic cyst growth might also be linked to indirect action of PAS by inhibiting IGF1.12, 15, 17 We and others have previously reported that all five SSTRs are localized to rat and human cholangiocytes.6, 7 Our data showing the decreased levels of SSTR1 and SSTR2 (but not SSTR3 and SSTR5) in cystic cholangiocytes are novel.

To this end, the most plausible explanation for the moderate therapeutic success seen in patients with PLD and PKD is that current somatostatin analogs target mainly SSTR2, the expression of which appears to be decreased in hepatic cysts. Native somatostatin and its synthetic analogs have the ability to regulate the expression levels of SSTRs by as yet not well understood mechanisms.21, 30 It has been suggested that up-regulation of SSTRs results in a longer lasting functional responses to agonist exposure.21 We showed that immunoreactivity of SSTR2 (in response to OCT and PAS) and SSTR1 (in response to PAS) is increased in cystic cholangiocytes. These changes in drug-induced receptor expression likely also contribute to the stronger suppressive effects of PAS because it binds to both SSTR1 and SSTR2.