The Novel Somatostatin Receptor 2/Dopamine Type 2 Receptor Chimeric Compound BIM-23A758 Decreases the Viability of Human GOT1 Midgut Carcinoid Cells

The majority of neuroendocrine tumors (NETs) of
thegastro-enteropancreatic system coexpress sornatostatin receptors
(SSTRs)and dopamine type 2 receptors (D2R), thus providing a
rationale for theuse of novel SSTR2/D2R chimeric compounds in NET
disease. Here weinvestigate the antitumor potential of the
SSTR2/D2R chimeric compoundsBIM-23A760 and BIM-23A758 in comparison
to the selective SSTR2 agonistBIM-23023 and the selective D2R
agonist BIM-53097 on human NET celllines of heterogeneous origin.
While having only minor effects on humanpancreatic and bronchus
carcinoid cells (BONI and NCI-H727), BIM-23A758induced significant
antitumor effects in human midgut carcinoid cells(GOT1). These
effects involved apoptosis induction as well as inhibitionof
mitogen-activated protein kinase and Akt signaling. Consistent
withtheir antitumor response to BIM-23A758, GOT1 cells showed
relativelyhigh expression levels of SSTR2 and D2R mRNA. In
particular, GOT1 cellshighly express the short transcript variant
of D2R. In contrast toBIM-23A758, the SSTR2/D2R chimeric compound
BIM-23A760 as well as theindividual SSTR2 and D2R agonistic
compounds BIM-23023 and BIM-53097induced no or only minor antitumor
responses in the examined NET celllines. Taken together, our
findings suggest that the novel SSTR2/D2Rchimeric compound
BIM-23A758 might be a promising substance for thetreatment of NETs
highly expressing SSTR2 and D2R. In particular, asufficient
expression of the short transcript variant of DR2 might playa
pivotal role for effective treatment.