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

Laura S Pradel1, Yu-Lin Ho1, Holger Gohlke1,2

  • 1Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.

International Journal of Molecular Sciences
|August 10, 2024
PubMed

Insights

Combining exemestane with alpha-lipoic acid shows promise for treating estrogen receptor-positive breast cancer. This novel strategy targets aberrant epigenetics, enhancing therapeutic outcomes by inducing apoptosis and inhibiting cancer cell proliferation.

Area of Science:

  • Oncology
  • Epigenetics
  • Pharmacology

Background:

  • Estrogen receptor (ER)-positive breast cancer treatment relies on anti-estrogenic therapies.
  • Therapeutic resistance necessitates novel strategies, including targeting epigenetic aberrations.
  • Histone deacetylase (HDAC) inhibitors and antioxidants are potential therapeutic agents.

Purpose of the Study:

  • To investigate the combination of exemestane (aromatase inhibitor) and alpha-lipoic acid (HDAC inhibitor/antioxidant) for ER-positive breast cancer.
  • To evaluate the HDAC inhibitory potential of alpha-lipoic acid enantiomers and dihydro-lipoic acid.
  • To assess the synergistic effects of exemestane and alpha-lipoic acid on cancer cells.

Main Methods:

  • Screening of alpha-lipoic acid and its derivatives for HDAC inhibition.
  • Determining the antiproliferative IC50 values of alpha-lipoic acid.
  • Assessing synergistic effects using Chou-Talalay method across various time points and assays (MTT, live-cell microscopy, caspase activation).

Main Results:

  • Alpha-lipoic acid demonstrated HDAC inhibition (micromolar range), with a preference for HDAC6.
  • Dihydro-lipoic acid showed slightly higher potency than alpha-lipoic acid.
  • Exemestane and alpha-lipoic acid exhibited synergistic antiproliferative effects, increasing apoptosis-related proteins and decreasing anti-apoptotic proteins.

Conclusions:

  • The combination of exemestane and alpha-lipoic acid presents a promising therapeutic strategy for ER-positive breast cancer.
  • Alpha-lipoic acid's ability to inhibit HDAC and induce apoptosis contributes to its efficacy.
  • This combination warrants further investigation for clinical application in breast cancer treatment.
Keywords:
alpha-lipoic acidaromatase inhibitorbreast cancercombination therapyendocrine therapyestrogen receptorexemestanehistone deacetylase inhibitorsynergy

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