Ivermectin-induced cell death of cervical cancer cells in vitro a consequence of precipitate formation in culture media

The anthelmintic ivermectin has been reported to possess anticancer and antiviral efficacy. However, the effective concentrations reported in vitro are near the predicted aqueous solubility limit for this hydrophobic drug. We observed that ivermectin-induced cell death in two cervical cancer cell lines correlated with the formation of solid ivermectin aggregates in both serum-free and serum-supplemented culture media. Filtration of ivermectin particles >0.2 mu m abolished these cytolytic effects in both cell lines. An inhibitory effect on cell proliferation persisted for filtered solutions, but only for ivermectin concentrations higher than reported to be clinically attainable in humans. In addition to the importance of distinguishing between free and bound drug in solution, our data emphasize the importance of acknowledging the likely solubility limit of hydrophobic drugs when assessing their in vitro cytotoxicity.