Pasireotide has been associated with
tumor shrinkage in patients with
Cushing's disease subjected to long term treatment. However, to date the implicated molecular mechanisms are poorly elucidated. Here, we tested
pasireotide-mediated
cytostatic and cytotoxic effects in
ACTH-secreting primary
tumor cultures and murine corticotroph tumor cell line, AtT-20 cells. We found
somatostatin receptor type 5 (SST5) expressed in 17 different
ACTH-secreting
tumors and SST2 detectable in 15 out of the 17 tissues.
Pasireotide caused a slight but significant in vitro inhibition of cell growth in 3 out of 6
ACTH-secreting primary cultures (-12.1 ± 4.3%, P < 0.01 at 10 nM), remarkably reduced phospho-ERK1/2 levels in 5 out of 8 samples (-36.4 ± 20.5%, P < 0.01 at 1 μM) and triggered an increase of
caspase 3/7 activity in 2 of 4
tumors (17 ± 3.6%, P < 0.05 at 1 μM). Accordingly, in AtT-20 cells,
pasireotide significantly inhibited cell proliferation (-10.5 ± 7.7% at 10 nM, P < 0.05; -13.9 ± 10.9% at 100 nM, P < 0.05; -26.8 ± 8.9% at 1 μM, P < 0.01). Similar antiproliferative actions were exerted by
BIM23206 and
BIM23120 (SST5&2 selective
ligands, respectively), whereas
octreotide was effective when used at 1 μM (-13.3 ± 9.1%, P < 0.05). Moreover, a reduction of phospho-ERK1/2 was observed upon
pasireotide and
BIM23206 treatment (-8.4 ± 28.6%, P < 0.01 and -51.4 ± 15.9%, P < 0.001 at 10 nM, respectively) but not after
octreotide and
BIM23120 incubation. Finally,
pasireotide was able to induce cell apoptosis in AtT-20 cells at lower concentration than
octreotide. Altogether these data indicate a downstream implication of SST5-mediated phospho-ERK1/2 inhibition by
pasireotide resulting in
ACTH-secreting
tumor cells proliferation reduction. Moreover, we describe for the first time a pro-apoptotic effect of
pasireotide in corticotrophs.