The Antioxidant and HDAC-Inhibitor α-Lipoic Acid Is Synergistic with Exemestane in Estrogen Receptor-Positive Breast Cancer Cells

被引：0
作者：
Pradel, Laura S. [1 ]
Ho, Yu-Lin [1 ]
Gohlke, Holger [1 ,2 ]
Kassack, Matthias U. [1 ]
机构：
[1] Heinrich Heine Univ Dusseldorf, Inst Pharmaceut & Med Chem, D-40225 Dusseldorf, Germany
[2] Forschungszentrum Julich, Inst Bio & Geosci IBG 4 Bioinformat, D-52425 Julich, Germany
来源：
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES | 2024年 / 25卷 / 15期
关键词：
breast cancer; estrogen receptor; endocrine therapy; histone deacetylase inhibitor; aromatase inhibitor; alpha-lipoic acid; exemestane; combination therapy; synergy; HISTONE DEACETYLASE INHIBITORS; PHASE-II; ENTINOSTAT; HALLMARKS; PLACEBO; AGENTS;
D O I：
10.3390/ijms25158455
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
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 alpha-lipoic acid in ER-positive breast cancer cells. First, the enantiomers and the racemic mixture of alpha-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-alpha-lipoic acid. The antiproliferative IC50 value of alpha-lipoic acid is in the 3-digit micromolar range. Notably, the combination of exemestane and alpha-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. alpha-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 alpha-lipoic acid is a promising novel treatment option for ER-positive breast cancer.
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页数：26
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