Serotoninergic receptor ligands improve Tamoxifen effectiveness on breast cancer cells
Maria Rosaria Ambrosio1,2, Elisa Magli3, Giuseppe Caliendo3
1Institute for Experimental Endocrinology and Oncology "G. Salvatore" - National Research Council (IEOS-CNR), Via Pansini 5, 80131, Naples, Italy.
Background:
Serotonin (or 5-Hydroxytryptamine, 5-HT) signals in mammary gland becomes dysregulated in cancer, also contributing to proliferation, metastasis, and angiogenesis. 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-HT2A and 5-HT2C 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; mRNA levels of CTGF and ABC transporters have been further measured by qPCR. Protein levels of 5-HT2C receptors have been analyzed by Western blot. All data were statistically analyzed using GraphPad Prism 7.
Results:
We found that treatment with SER for 72 h reduced viability of BC cells. SER were more effective on MCF7 ER+ cells (IC50 range 10.2 μM - 99.2 μM) compared to SKBR3 (IC50 range 43.3 μM - 260 μM) and MDA-MB231 BC cells (IC50 range 91.3 μM - 306 μM). This was paralleled by accumulation of cells in G0/G1 phase of cell cycle. Next, we provided evidence that two ligands, SER79 and SER68, improved the effectiveness of Tamoxifen treatment in MCF7 cells and modulated the expression of CTGF, without affecting viability of MCF10A non-cancer breast epithelial cells. In a cell model of Tamoxifen resistance, SER68 also restored drug effect independently of CTGF.
Conclusions:
These results identified serotoninergic receptor ligands potentially usable in combination with Tamoxifen to improve its effectiveness on ER+ BC patients.
Insights
Novel compounds targeting serotonin signaling show promise for breast cancer treatment. These serotoninergic receptor ligands enhance Tamoxifen effectiveness in ER+ breast cancer cells, offering new therapeutic strategies.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Serotonin (5-Hydroxytryptamine, 5-HT) signaling is dysregulated in breast cancer (BC), promoting tumor growth and metastasis.
- Targeting 5-HT receptors, particularly 5-HT2A and 5-HT2C, is a potential therapeutic strategy for BC.
- Previously synthesized serotoninergic receptor ligands (SER) exhibit high affinity and selectivity for these key receptors.
Purpose of the Study:
- To investigate the effects of 10 novel SER compounds on the viability of different BC cell lines (MCF7, SKBR3, MDA-MB231).
- To evaluate the potential of these SER compounds to modulate Tamoxifen responsiveness in estrogen receptor-positive (ER+) BC cells.
- To explore the impact of SER compounds on cell cycle progression and specific gene/protein expression related to BC.
Main Methods:
- Cell viability assessed using the sulforhodamine B assay.
- Cell cycle analysis performed via flow cytometry.
- Gene and protein expression of 5-HT receptors and Connective Tissue Growth Factor (CTGF) analyzed by RT-PCR, qPCR, and Western blot.
Main Results:
- Treatment with SER compounds reduced BC cell viability, with greater efficacy in MCF7 ER+ cells.
- SER compounds induced cell cycle arrest at the G0/G1 phase.
- Two ligands, SER79 and SER68, enhanced Tamoxifen effectiveness in MCF7 cells and modulated CTGF expression without affecting normal breast cells.
- SER68 restored Tamoxifen efficacy in a Tamoxifen-resistant cell model, independent of CTGF.
Conclusions:
- Novel serotoninergic receptor ligands demonstrate significant anti-cancer effects on breast cancer cells.
- Specific SER compounds (SER79, SER68) show potential for combination therapy with Tamoxifen to improve treatment outcomes in ER+ BC patients.
- These findings highlight the therapeutic potential of targeting serotonin signaling pathways in breast cancer management.
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