Effects of novel somatostatin-dopamine chimeric drugs in 2D and 3D cell culture models of neuroendocrine tumors.

Control of symptoms related to hormonal hypersecretion by functioning neuroendocrine tumors (NETs) is challenging. New therapeutic options are required. Since novel in vitro tumor models seem to better mimic the tumor in vivo conditions, we aimed to study the effect of somatostatin and dopamine receptor agonists (octreotide and cabergoline, respectively) and novel somatostatin-dopamine chimeric multi-receptor drugs (BIM-065, BIM-23A760) using 2D (monolayer) and 3D (spheroids) cultures.

METHODS: Dose-response studies in 2D and 3D human pancreatic NET cell cultures (BON-1 and QGP-1) were performed under serum-containing and serum-deprived conditions. Cell proliferation, somatostatin and dopamine receptors expression (sst and D2R), apoptosis, lactate dehydrogenase, as well as serotonin and chromogranin-A (CgA) release were assessed.

RESULTS: 3D-cultures of BON-1/QGP-1 allowed better cell survival than 2D-cultures in serum-deprived conditions. Sst and D2R mRNA levels were significantly higher in the 3D-model vs. 2D-model. Octreotide/cabergoline/BIM-065/BIM-23A760 treatment did not affect cell-growth or spheroid size. In BON-1 2D-cultures, only BIM-23A760 significantly inhibited CgA release, being this effect more pronounced in 3D-cultures. In BON-1 2D-cultures, cabergoline/BIM-065/BIM-23A760 treatment decreased serotonin release (maximal effect up to 40%), being this effect again more potent in 3D-cultures (up to 67% inhibition; with BIM-23A760 having the most potent effects). In QGP-1, cabergoline/BIM-065 treatment decreased serotonin release only in the 3D-model.

CONCLUSIONS: Cultures of NET 3D-spheroids represent a promising method for evaluating cell-proliferation and secretion in NET cell-line models. Compared to 2D-models, 3D-models grow relatively serum-independent. In 3D-model, sst-D2R multi-receptor targeting drugs inhibit CgA and serotonin secretion, but not NET cell-growth.