Busonero Claudia, Leone Stefano, Bianchi Fabrizio, Maspero Elena, Fiocchetti Marco, Palumbo Orazio, Cipolletti Manuela, Bartoloni Stefania, Acconcia Filippo
Department of Sciences, Section Biomedical Sciences and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146 Rome, Italy.
Cancer Biomarkers Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo (FG), Italy.
Cancers (Basel). 2020 Dec 19;12(12):3840. doi: 10.3390/cancers12123840.
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.
雌激素受体α阳性乳腺癌（BC）通常采用内分泌治疗。长期内分泌治疗常导致转移性疾病（MBC），目前仍缺乏标准化的有效治疗方法。因此，原发性和转移性乳腺癌的治疗需要新药。在此，我们报告美国食品药品监督管理局（FDA）批准的药物哇巴因和地高辛可诱导ERα降解，并在原发性和转移性乳腺癌细胞模型中抑制细胞增殖。哇巴因和地高辛激活细胞蛋白酶体，促使ERα降解，从而抑制17β-雌二醇信号传导，诱导细胞周期在G2期阻滞，并引发细胞凋亡。值得注意的是，这些作用与抑制钠钾泵无关。哇巴因和地高辛的抗增殖作用在多种癌症模型（如肿瘤球体和异种移植模型）中也有体现。此外，基因谱分析表明，这些药物可下调与内分泌治疗耐药相关基因的表达。因此，哇巴因和地高辛表现出“抗雌激素”样药物的特性，是原发性和转移性乳腺癌治疗的有吸引力的候选药物。
