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Ivermectin exhibits potent anti-mitotic activity
Shoaib Ashraf1, Roger Prichard1
1Institute of Parasitology, McGill University-Macdonald Campus, Sainte-Anne-de-Bellevue, H9X 3V9 Quebec, Canada.
Abstract:
Ivermectin (IVM) is a pharmaceutical used as an anti-parasitic drug in livestock, companion animals and humans. The primary site of action of IVM is believed to be glutamate-gated chloride channels (GluCls). However we have recently reported a direct interaction between IVM and nematode tubulin with micromolar affinity. Here we report that IVM also interacts with mammalian tubulin. To test this possibility, we used the tubulin polymerization assay and found that IVM increased the degree of polymerization of mammalian tubulin. Furthermore when HeLa cells were exposed to IVM it stabilized the mammalian tubulin against the depolymerizing effects of cold temperatures, and prevented the replication of the HeLa cells in vitro. However, the IVM-induced inhibition of HeLa cell division was reversible. The data suggests that mammalian microtubules bound IVM and were stabilized by IVM at micromolar concentrations. IVM may thus affect the dynamics of tubulin polymerization and depolymerization, which in turn can result in cell death. Given that IVM is already approved for use in humans, its development as an anti-mitotic is a potentially appealing option.
Insights
Ivermectin (IVM) interacts with mammalian tubulin, stabilizing microtubules and inhibiting cell division. This anti-mitotic effect is reversible, suggesting potential therapeutic applications.
Area of Science:
- Pharmacology
- Cell Biology
- Biochemistry
Background:
- Ivermectin (IVM) is an established anti-parasitic drug.
- Its primary mechanism involves glutamate-gated chloride channels (GluCls).
- Recent findings suggest IVM also interacts with nematode tubulin.
Purpose of the Study:
- To investigate the interaction of Ivermectin (IVM) with mammalian tubulin.
- To determine the effects of IVM on mammalian microtubule dynamics and cell division.
- To explore the potential of IVM as an anti-mitotic agent.
Main Methods:
- Tubulin polymerization assays were conducted.
- HeLa cells were exposed to IVM and subjected to cold-induced depolymerization.
- Cell replication and division were monitored in vitro.
Main Results:
- IVM demonstrated direct interaction with mammalian tubulin.
- IVM increased mammalian tubulin polymerization.
- IVM stabilized microtubules against depolymerization and inhibited HeLa cell replication reversibly.
Conclusions:
- Mammalian microtubules bind and are stabilized by IVM at micromolar concentrations.
- IVM affects tubulin polymerization/depolymerization dynamics, leading to cell death.
- IVM's anti-mitotic properties warrant further investigation for therapeutic development.
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