Serotoninergic receptor ligands improve Tamoxifen effectiveness on breast cancer cells

被引：8

作者：

Ambrosio, Maria Rosaria ^{[1
,2
]}

Magli, Elisa ^{[3
]}

Caliendo, Giuseppe ^{[3
]}

Sparaco, Rosa ^{[3
]}

Massarelli, Paola ^{[4
]}

D'Esposito, Vittoria ^{[1
,2
]}

Migliaccio, Teresa ^{[2
]}

Mosca, Giusy ^{[2
]}

Fiorino, Ferdinando ^{[3
]}

Formisano, Pietro ^{[1
,2
]}

机构：

[1] Natl Res Council IEOS CNR, Inst Expt Endocrinol & Oncol G Salvatore, Via Pansini 5, I-80131 Naples, Italy

[2] Univ Naples Federico II DiSMeT UniNa, Dept Translat Med, Via Pansini 5, I-80131 Naples, Italy

[3] Univ Naples Federico II UniNa, Dept Pharm, Via Montesano 49, I-80131 Naples, Italy

[4] Univ Siena, Dept Med Surg & Neurosci, Str Scotte 6, I-53100 Siena, Italy

来源：

BMC CANCER | 2022年 / 22卷 / 01期

关键词：

Serotonin; Breast cancer; Serotoninergic receptor ligands; Tamoxifen resistance; Connective Tissue Growth Factor; ACTIVATED PROTEIN-KINASE; IN-VITRO; PHARMACOLOGICAL EVALUATION; SEROTONERGIC REGULATION; NUCLEUS SYNTHESIS; 5-HT1A RECEPTOR; INHIBITOR;

D O I：

10.1186/s12885-021-09147-y

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 mu M - 99.2 mu M) compared to SKBR3 (IC50 range 43.3 mu M - 260 mu M) and MDA-MB231 BC cells (IC50 range 91.3 mu M - 306 mu M). 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.

引用

页数：14

共 43 条

[41] Serotonin activates glycolysis and mitochondria biogenesis in human breast cancer cells through activation of the Jak1/STAT3/ERK1/2 and adenylate cyclase/PKA, respectively [J].