Repurposing methuosis-inducing anticancer drugs for anthelmintic therapy

Abstract

Drug-resistant parasitic nematodes pose a grave threat to plants, animals, and humans. An innovative paradigm for treating parasitic nematodes is emphasized in this opinion. This approach relies on repurposing methuosis (a death characterized by accumulation of large vacuoles) inducing anticancer drugs as anthelmintics. We review drugs/chemicals that have shown to kill nematodes or cancerous cells by inducing multiple vacuoles that eventually coalesce and rupture. This perspective additionally offers a succinct summary on Structure-Activity Relationship (SAR) of methuosis-inducing small molecules. This strategy holds promise for the development of broad-spectrum anthelmintics, shedding light on shared molecular mechanisms between cancer and nematodes in response to these inducers, thereby potentially transforming both therapeutic domains.

Fig 1. Molecular pathways that lead to methuosis in cancer cells.

Briefly, Lamellipodia, or ruffles, allow nutrients and liquid tracer to enter cells, forming macropinocytic sinks, which coalesce into macropinosomes. The merger of macropinosomes produces giant vacuoles, which rupture and cause the death of cells by methuosis (refer text for details).

Fig 2

Organic acids with mono- or dicarboxy groups and indole derivatives with iodine or fluorine that cause vacuoles in nematodes (a), electronegative interactions between iodine and fluorine in 5F4IPP may be responsible for better glutamate-gated chloride channel (GluCl) receptor interactions and suppressed methuosis (b), and death phenotypes in pinewood nematode treated with 5-iodoindole (c).