Ouabain and Digoxin Activate the Proteasome and the Degradation of the ERα in Cells Modeling Primary and Metastatic Breast Cancer

Cancers

Fabrizio Bianchi¹  Claudia Busonero²  Stefania Bartoloni²  Manuela Cipolletti²  Stefano Leone²  Filippo Acconcia²  Marco Fiocchetti²  Orazio Palumbo³  Elena Maspero⁴ 

[1] Cancer Biomarkers Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo (FG), Italy;Department of Sciences, Section Biomedical Sciences and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146 Rome, Italy;Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo (FG), Italy;Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), 20139 Milan, Italy;

关键词: 17β-estradiol;    estrogen receptor;    breast cancer;    proteasome;    ouabain;    digoxin;   

DOI  :  10.3390/cancers12123840

来源: DOAJ

【 摘 要 】

Estrogen receptor α expressing breast cancers (BC) are classically treated with endocrine therapy. Prolonged endocrine therapy often results in a metastatic disease (MBC), for which a standardized effective therapy is still lacking. Thus, new drugs are required for primary and metastatic BC treatment. Here, we report that the Food and Drug Administration (FDA)-approved drugs, ouabain and digoxin, induce ERα degradation and prevent proliferation in cells modeling primary and metastatic BC. Ouabain and digoxin activate the cellular proteasome, instigating ERα degradation, which causes the inhibition of 17β-estradiol signaling, induces the cell cycle blockade in the G2 phase, and triggers apoptosis. Remarkably, these effects are independent of the inhibition of the Na/K pump. The antiproliferative effects of ouabain and digoxin occur also in diverse cancer models (i.e., tumor spheroids and xenografts). Additionally, gene profiling analysis reveals that these drugs downregulate the expression of genes related to endocrine therapy resistance. Therefore, ouabain and digoxin behave as ‘anti-estrogen’-like drugs, and are appealing candidates for the treatment of primary and metastatic BCs.

【 授权许可】

Unknown