Ivermectin Induces Apoptosis Through Mitochondrial Dysfunction in CML Cells

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A recent study sought to determine the effect of ivermectin against CML cells, whether ivermectin can sensitize cells to BCR-ABL TKIs, and its mechanism of action.
A recent study sought to determine the effect of ivermectin against CML cells, whether ivermectin can sensitize cells to BCR-ABL TKIs, and its mechanism of action.

Ivermectin, an antihelminthic, causes apoptosis of chronic myeloid leukemia (CML) cells and CML CD34 stem/progenitor cells through oxidative stress and mitochondrial dysfunction, according to a study published in Biochemical and Biophysical Research Communications.1

Although BCR-ABL–targeted tyrosine kinase inhibitors (TKIs) are highly effective achieving remission among patients with CML, CML CD34 stem/progenitor cells persist. The purpose of this study was to determine the effect of ivermectin against CML cells, whether ivermectin can sensitize cells to BCR-ABL TKIs, and its mechanism of action.

The in vitro studies used CML CD34 stem/progenitor cells harvested from patients with CML and cultured human K562 CML cells to evaluate apoptosis, mitochondrial function, and reactive oxygen species (ROS).

Treatment with ivermectin resulted in caspase-dependent apoptosis of CD34 and K562 CML cells, but not normal CD34 cells. Apoptosis occurred in about 30% of CML CD34 or K562 CML cells when treated with a TKI or ivermectin monotherapy. The combination of ivermectin and a TKI, however, increased the frequency of apoptosis to about 95%, suggesting that the combination has a synergistic effect.

Ivermectin decreased basal and maximal mitochondrial respiration in CML CD34, K562 CML cells, and normal cells, and decreased the mitochondrial respiratory complex I in CML and normal CD34 cells. Ivermectin also increased levels of ROS and superoxide, both markers of mitochondrial dysfunction.

To determine if the in vitro findings could be replicated in vivo, SCID mice with CML xenografts were treated with ivermectin alone or in combination with dasatinib. Though ivermectin monotherapy decreased CML tumor growth in a dose-dependent manner, greater inhibition was achieved with the combination.

The authors wrote that their data “provides the fundamental evidence to repurpose ivermectin for CML treatment,” and noted that their findings highlight “the therapeutic value of targeting mitochondria respiration in CML.”

Reference

  1. Wang J, Xu Y, Wan H, Hu J. Antibiotic ivermectin selectively induces apoptosis in chronic myeloid leukemia through inducing mitochondrial dysfunction and oxidative stress. Biochem Biophy Res Commun. 2018;497:241-247. doi: 10.1016/j.bbrc.2018.02.063

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