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

Summary

This review examines a group of rare fungal compounds called incisterols, with a focus on demethylincisterol A3 (DM-A3), which has shown promise as an anticancer agent. DM-A3 works through multiple mechanisms including blocking cancer cell signaling pathways, inhibiting specific enzymes, and reducing inflammation. The compound has demonstrated effectiveness against various cancer types in laboratory studies and showed tumor-reducing effects in animal models, suggesting potential for future cancer therapy development.

Background

Highly degraded sterols belonging to the incisterol group have been identified in microorganisms, with demethylincisterol A3 (DM-A3) showing marked antitumor properties. Since the initial discovery of incisterol from a marine sponge in the 1990s, more than 30 incisterol-type natural products have been identified, primarily from fungi.

Objective

To provide a comprehensive overview of incisterol-type natural products, their bio-origin, chemical synthesis, pharmacological properties, and mechanism of action of the lead compound DM-A3. The review aims to promote further research into this neglected group of anticancer agents.

Results

Over 30 incisterol-type natural products identified from approximately 50 fungal species. DM-A3 demonstrated potent cytotoxic activity (IC50 range 0.17 nM to 28.45 μM depending on assay conditions) and antitumor efficacy in vivo. Three main mechanisms identified: Wnt pathway inhibition, SHP2 inhibition (IC50 = 6.75 µM), and acetylcholinesterase inhibition (IC50 = 11.16 µM).

Conclusion

DM-A3 represents a promising anticancer agent with a unique dual SHP2/AchE inhibitory mechanism coupled with anti-inflammatory properties through the cholinergic pathway. Further investigation of pharmacokinetics, toxicity, and structure-activity relationships of incisterol derivatives is warranted before clinical development.
  • Published in:Life (Basel),
  • Study Type:Review,
  • Source: PMID: 41157310, DOI: 10.3390/life15101638
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