R-etodolac is a more potent Wnt signaling inhibitor than enantiomer, S-etodolac

JoAnn S Roberts; Chao Ma; Sarah Y T Robertson; Stephen Kang; Christiana S Han; Sophie X Deng; Jie J Zheng

doi:10.1016/j.bbrep.2022.101231

R-etodolac is a more potent Wnt signaling inhibitor than enantiomer, S-etodolac

Biochem Biophys Rep. 2022 Feb 19:30:101231. doi: 10.1016/j.bbrep.2022.101231. eCollection 2022 Jul.

Authors

JoAnn S Roberts¹, Chao Ma¹, Sarah Y T Robertson¹, Stephen Kang¹, Christiana S Han¹, Sophie X Deng^{1

2}, Jie J Zheng^{1

2}

Affiliations

¹ Stein Eye Institute, Department of Ophthalmology, David Geffen School of Medicine at University of California, Los Angeles, CA, 90095, USA.
² Molecular Biology Institute, University of California, Los Angeles, CA, 90095, USA.

Abstract

Etodolac is an FDA-approved nonsteroidal anti-inflammatory drug (NSAID) used to treat a variety of inflammatory diseases. The drug is administered as a racemate (50/50 mixture of R- and S- enantiomers), however, studies have shown that the two enantiomers have distinct biologic and pharmacokinetic differences. Wnt signaling, which plays key roles in cell proliferation, polarity, and differentiation, has been shown to be inhibited by R-etodolac; however, comparative analyses of R- and S-etodolac in this function have not been conducted. We used in silico molecular docking and TOPflash functional biologic assays to compare R- and S-enantiomers effect on Wnt signaling inhibition. Further, we used a cultivated limbal stem epithelial cell (cLSCs) model to investigate enantiospecific changes in the colony-forming efficiency (CFE) of cLSCs. The data shows that R-etodolac is a more potent inhibitor of Wnt signaling. In addition, consistently, while both enantiomers demonstrate a dose-dependent decrease in CFE of cLSCs, R-etodolac is a more potent inhibitor.

Keywords: Limbal stem epithelial cells; R-etodolac; S-etodolac; Wnt signaling.

Abstract

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