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Withanolide Derivative 2,3-Dihydro-3β-methoxy Withaferin-A Modulates the Circadian Clock via Interaction with
Tatsunosuke Tomita1, Renu Wadhwa1, Sunil C Kaul1
1AIST-INDIA DAILAB, Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Higashi 1-1-1, Tsukuba 305-8565, Japan.
Journal of Natural Products
|June 21, 2021
Summary
A novel withanolide derivative, 2,3-dihydro-3β-methoxy withaferin-A (3βmWi-A), was found to lengthen circadian clock periods in cancer cells and normal fibroblasts. This compound modulates key clock genes, acting as an inverse agonist for RORa.
Area of Science:
- Pharmacology
- Chronobiology
- Molecular Biology
Background:
- Withanolide derivatives, found in Ayurvedic medicine, possess diverse biological activities.
- Circadian rhythms are crucial for cellular and organismal health, and their disruption is linked to disease.
- Ashwagandha (Withania somnifera) is a source of withanolides, including withaferin-A (Wi-A).
Purpose of the Study:
- To investigate the effect of 2,3-dihydro-3β-methoxy withaferin-A (3βmWi-A), a Wi-A derivative, on circadian clock function.
- To elucidate the molecular mechanisms underlying 3βmWi-A's impact on circadian rhythms.
Main Methods:
- Assessing the effect of 3βmWi-A on circadian period length in cancer cells (Sarcoma 180) and normal fibroblasts (NIH3T3, MEF).
- Measuring mRNA expression and promoter activity of core circadian clock genes (Bmal1, Rora, Nr1d1) following 3βmWi-A treatment.
- Characterizing 3βmWi-A's interaction with RORa using biochemical assays (IC50, Kd).
Main Results:
- 3βmWi-A dose-dependently elongated circadian rhythms in both cancer and normal cells.
- The compound upregulated Bmal1, Rora, and Nr1d1 mRNA expression and promoter activity.
- 3βmWi-A acted as an inverse agonist for RORa with a measured IC50 of 11.3 μM and weak direct interaction (Kd, 5.9 μM).
Conclusions:
- 3βmWi-A is a novel modulator of circadian rhythms.
- The compound's effects are mediated through the regulation of core clock gene expression and interaction with RORa.
- This finding opens new avenues for therapeutic interventions targeting circadian rhythm disorders.
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