Serotoninergic receptor ligands improve Tamoxifen effectiveness on breast cancer cells

BMC Cancer

Paola Massarelli¹  Giuseppe Caliendo²  Ferdinando Fiorino²  Rosa Sparaco²  Elisa Magli²  Teresa Migliaccio³  Giusy Mosca³  Maria Rosaria Ambrosio⁴  Vittoria D’Esposito⁴  Pietro Formisano⁴ 

[1] Department of Medicine, Surgery and Neuroscience, University of Siena, Strada delle Scotte 6 –, 53100, Siena, Italy;Department of Pharmacy, University of Naples “Federico II” (UniNa), Via Montesano 49 -, 80131, Naples, Italy;Department of Translational Medicine, University of Naples “Federico II” (DiSMeT-UniNa), Via Pansini 5, 80131, Naples, Italy;Institute for Experimental Endocrinology and Oncology “G. Salvatore” – National Research Council (IEOS-CNR), Via Pansini 5, 80131, Naples, Italy;Department of Translational Medicine, University of Naples “Federico II” (DiSMeT-UniNa), Via Pansini 5, 80131, Naples, Italy;

关键词: Serotonin;    Breast cancer;    Serotoninergic receptor ligands;    Tamoxifen resistance;    Connective Tissue Growth Factor;   

DOI  :  10.1186/s12885-021-09147-y

来源: Springer

【 摘 要 】

BackgroundSerotonin (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.MethodsCell 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.ResultsWe 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.ConclusionsThese results identified serotoninergic receptor ligands potentially usable in combination with Tamoxifen to improve its effectiveness on ER+ BC patients.

【 授权许可】

CC BY