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Anticancer Activity of Demethylincisterol A3 and Related Incisterol-Type Fungal Products

Summary

This review examines a special group of fungal compounds called incisterols, with focus on demethylincisterol A3 (DM-A3), which shows promise as a cancer-fighting agent. DM-A3 works through multiple mechanisms: it blocks cancer cell growth pathways, inhibits specific cancer-promoting proteins, and has anti-inflammatory effects. The compound has shown strong activity against various cancer types in laboratory and animal studies, making it a candidate for further development as a potential cancer therapy.

Background

Incisterol-type natural products are highly degraded sterols belonging to a unique category of compounds identified from microorganisms, particularly fungi. More than 30 incisterol-type natural products have been discovered since the initial discovery of incisterol from a marine sponge in the 1990s, with demethylincisterol A3 (DM-A3) being the leading compound in the family.

Objective

This review provides a comprehensive overview of incisterol-type natural products and their pharmacological properties, with particular focus on demethylincisterol A3 (DM-A3) and its anticancer mechanisms of action to promote further research into this neglected group of anticancer agents.

Results

Analysis revealed three main mechanisms of DM-A3 anticancer activity: inhibition of β-catenin and Wnt signaling pathway, selective inhibition of tyrosine phosphatase SHP2 (IC50 = 6.75 µM), and blockade of α7nAchR activation coupled with acetylcholinesterase inhibition (IC50 = 11.16 µM). DM-A3 demonstrated potent cytotoxic activity against various cancer cell lines with marked antitumor activity in mice bearing HeLa and HepG2 tumors.

Conclusion

DM-A3 emerges as the most promising incisterol derivative with unique dual SHP2/AchE inhibitory activity and multimodal mechanism of action. The compound warrants further investigation as an anticancer agent, with emphasis on pharmacokinetic properties and toxicity profiling prior to expanded in vivo studies.
  • Published in:Life (Basel),
  • Study Type:Review,
  • Source: PMID: 41157310, DOI: 10.3390/life15101638
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