PDF(Pubmed)
Abstract：
Anti-estrogenic therapy is established in the management of estrogen receptor (ER)-positive breast cancer. However, to overcome resistance and improve therapeutic outcome, novel strategies are needed such as targeting widely recognized aberrant epigenetics. The study aims to investigate the combination of the aromatase inhibitor exemestane and the histone deacetylase (HDAC) inhibitor and antioxidant α-lipoic acid in ER-positive breast cancer cells. First, the enantiomers and the racemic mixture of α-lipoic acid, and rac-dihydro-lipoic acid were investigated for HDAC inhibition. We found HDAC inhibitory activity in the 1-3-digit micromolar range with a preference for HDAC6. Rac-dihydro-lipoic acid is slightly more potent than rac-α-lipoic acid. The antiproliferative IC50 value of α-lipoic acid is in the 3-digit micromolar range. Notably, the combination of exemestane and α-lipoic acid resulted in synergistic behavior under various incubation times (24 h to 10 d) and readouts (MTT, live-cell fluorescence microscopy, caspase activation) analyzed by the Chou-Talalay method. α-lipoic acid increases mitochondrial fusion and the expression of apoptosis-related proteins p21, APAF-1, BIM, FOXO1, and decreases expression of anti-apoptotic proteins survivin, BCL-2, and c-myc. In conclusion, combining exemestane with α-lipoic acid is a promising novel treatment option for ER-positive breast cancer.
摘要：
在雌激素受体（ER）阳性乳腺癌的治疗中建立了抗雌激素疗法。然而,为了克服耐药性并改善治疗效果，需要新的策略,例如针对广泛认可的异常表观遗传学.本研究旨在探讨芳香化酶抑制剂依西美坦和组蛋白去乙酰化酶（HDAC）抑制剂和抗氧化剂α-硫辛酸在ER阳性乳腺癌细胞中的联合作用。首先,α-硫辛酸的对映体和外消旋混合物，研究了rac-二氢-硫辛酸对HDAC的抑制作用。我们发现HDAC抑制活性在1-3位数微摩尔范围内,优选HDAC6。Rac-二氢-硫辛酸比rac-α-硫辛酸略强。α-硫辛酸的抗增殖IC50值在3位数微摩尔范围内。值得注意的是,依西美坦和α-硫辛酸的组合在不同的孵育时间(24h至10d)和读数(MTT，活细胞荧光显微镜，半胱天冬酶激活)通过Chou-Talalay方法分析。α-硫辛酸增加线粒体融合和凋亡相关蛋白p21、APAF-1、BIM、FOXO1，并降低抗凋亡蛋白survivin的表达，BCL-2和c-myc。总之,联合使用依西美坦和α-硫辛酸是ER阳性乳腺癌的一种有前景的新型治疗选择.
