Cipolletti Manuela, Bartoloni Stefania, Busonero Claudia, Parente Martina, Leone Stefano, Acconcia Filippo
Department of Sciences, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146 Rome, Italy.
Int J Mol Sci. 2021 Mar 13;22(6):2915. doi: 10.3390/ijms22062915.
17β-estradiol (E2) exerts its physiological effects through the estrogen receptor α (i.e., ERα). The E2:ERα signaling allows the regulation of cell proliferation. Indeed, E2 sustains the progression of ERα positive (ERα+) breast cancers (BCs). The presence of ERα at the BC diagnosis drives their therapeutic treatment with the endocrine therapy (ET), which restrains BC progression. Nonetheless, many patients develop metastatic BCs (MBC) for which a treatment is not available. Consequently, the actual challenge is to complement the drugs available to fight ERα+ primary and MBC. Here we exploited a novel anti-estrogen discovery platform to identify new Food and Drug Administration (FDA)-approved drugs inhibiting E2:ERα signaling to cell proliferation in cellular models of primary and MBC cells. We report that the anti-fungal drugs clotrimazole (Clo) and fenticonazole (Fenti) induce ERα degradation and prevent ERα transcriptional signaling and proliferation in cells modeling primary and metastatic BC. The anti-proliferative effects of Clo and Fenti occur also in 3D cancer models (i.e., tumor spheroids) and in a synergic manner with the CDK4/CDK6 inhibitors palbociclib and abemaciclib. Therefore, Clo and Fenti behave as "anti-estrogens"-like drugs. Remarkably, the present "anti-estrogen" discovery platform represents a valuable method to rapidly identify bioactive compounds with anti-estrogenic activity.
17β-雌二醇（E2）通过雌激素受体α（即ERα）发挥其生理作用。E2:ERα信号传导可调节细胞增殖。实际上，E2维持ERα阳性（ERα+）乳腺癌（BC）的进展。BC诊断时ERα的存在决定了其采用内分泌治疗（ET），这种治疗可抑制BC进展。然而，许多患者会发展为转移性BC（MBC），对此尚无有效治疗方法。因此，当前的挑战是补充现有的用于治疗ERα+原发性和MBC的药物。在此，我们利用了一个新型抗雌激素发现平台，以识别新的美国食品药品监督管理局（FDA）批准的药物，这些药物可在原发性和MBC细胞的细胞模型中抑制E2:ERα信号传导对细胞增殖的影响。我们报告称，抗真菌药物克霉唑（Clo）和芬替康唑（Fenti）可诱导ERα降解，并阻止ERα在模拟原发性和转移性BC的细胞中的转录信号传导和增殖。Clo和Fenti的抗增殖作用在三维癌症模型（即肿瘤球体）中也会出现，并且与CDK4/CDK6抑制剂帕博西尼和阿贝西利协同发挥作用。因此，Clo和Fenti表现为类似“抗雌激素”的药物。值得注意的是，当前的“抗雌激素”发现平台是一种快速识别具有抗雌激素活性生物活性化合物的有价值方法。
