AZD4547 and calcitriol synergistically inhibited BT-474 cell proliferation while modified stemness and tumorsphere formation.
J Steroid Biochem Mol Biol
; 223: 106132, 2022 Oct.
Article
em En
| MEDLINE
| ID: mdl-35659529
ABSTRACT
Fibroblast growth factor receptor (FGFR) overamplification/activation in cancer leads to increased cell proliferation. AZD4547, a FGFR selective inhibitor, hinders breast cancer cells growth. Although luminal B breast tumors may respond to chemotherapy and endocrine therapy, this subtype is associated with poor prognosis, inadequate response and/or acquired drug resistance. Calcitriol, the vitamin D most active metabolite, exerts anti-neoplastic effects and enhances chemotherapeutic drugs activity. In this study, we sought to decrease the concentration of AZD4547 needed to inhibit the luminal-B breast cancer cell line BT-474 proliferation by its combination with calcitriol. Anti-proliferative inhibitory concentrations, combination index and dose-reduction index were analyzed from Sulforhodamine B assays. Western blot and qPCR were used to study FGFR molecular targets. The compound's ability to inhibit BT-474 cells tumorigenic capacity was assessed by tumorspheres formation. Results:
BT-474 cells were dose-dependently growth-inhibited by calcitriol and AZD4547 (IC50 = 2.9 nM and 3.08 µM, respectively). Calcitriol at 1 nM synergistically improved AZD4547 antiproliferative effects, allowing a 2-fold AZD4547 dose-reduction. Mechanistically, AZD4547 downregulated p-FGFR1, p-Akt and tumorsphere formation. Calcitriol also decreased tumorspheres, while induced cell differentiation. Both compounds inhibited MYC and CCND1 expression, as well as ALDH, a stemness marker that positively correlated with FGFR1 and negatively with VDR expression in breast cancer transcriptomic data. In conclusion, the drugs impaired self-aggregation capacity, reduced stemness features, induced cell-differentiation and when combined, synergistically inhibited cell proliferation. Overall, our results suggest that calcitriol, at low pharmacological doses, may be a suitable candidate to synergize AZD4547 effects in luminal B breast tumors, allowing to reduce dose and adverse effects.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias da Mama
/
Antineoplásicos
Tipo de estudo:
Prognostic_studies
Limite:
Female
/
Humans
Idioma:
En
Revista:
J Steroid Biochem Mol Biol
Assunto da revista:
BIOLOGIA MOLECULAR
/
BIOQUIMICA
Ano de publicação:
2022
Tipo de documento:
Article