Serotoninergic Receptor Ligands Improve Tamoxifen Effectiveness on Breast Cancer Cells

Background: The tightly regulated pattern of serotonin (or 5-Hydroxytryptamine, 5-HT) in mammary gland becomes dysregulated in cancer, also contributing to proliferation, metastasis and angiogenesis. Antagonists of serotonin receptors or inhibitors of serotonin reuptake/synthesis may be co-prescribed with Tamoxifen in estrogen receptor-positive (ER + ) tumors, and may modulate its efficacy. Thus, the discovery of novel compounds targeting serotonin signaling may contribute to tailor new therapeutic strategies usable in combination with endocrine therapies. We have previously synthesized serotoninergic receptor ligands (SER) with high affinity and selectivity towards 5-HT 2A and 5-HT 2C receptors, the main mediators of mitogenic effect of serotonin in breast cancer (BC). Here, we investigated the effect of 10 SER on viability of MCF7, SKBR3 and MDA-MB231 BC cells and focused on their potential ability to affect Tamoxifen responsiveness in ER + cells. Methods: : Cell viability has been assessed by sulforhodamine B assay. Cell cycle has been analyzed by flow cytometry. Gene expression of 5-HT receptors and Connective Tissue Growth Factor (CTGF) has been checked by RT-PCR; CTGF mRNA levels have been measured by qPCR. All data were statistically analyzed using GraphPad Prism 7. Results: : We found that SER were more effective on MCF7 ER + cells (IC 50 range 10.2µM - 99.2µM) compared to SKBR3 (IC 50 range 43.3µM - 260µM) and MDA-MB231 BC cells (IC 50 range 91.3µM - 306µM). Next, we provided evidence that two ligands, SER79 and SER68, improved the effectiveness of Tamoxifen treatment in MCF7 BC cells and modulated the expression of CTGF . Moreover, in a cell model of Tamoxifen-resistance, SER79 and SER68 restored drug responsiveness and reduced CTGF levels. Conclusions: : These results identified new compounds potentially usable in combination with Tamoxifen to improve its effectiveness on ER + BC patients.