Purpose Female breast cancer is the most prevalent cancer worldwide. Emerging evidence shows that simvastatin (SIM) has promising anticancer activities. However, the underlying mechanisms are not fully elucidated. Increasing reports imply statins can modulate ferroptosis through disrupting reactive oxygen species (ROS) and glutathione peroxidase enzyme (GPX4) levels. However, whether ferroptosis contributes to SIM anticancer activity, especially regarding GPX4 is unclear. Moreover, poor aqueous SIM solubility hinders its delivery in adequate levels to tumor sites. Meanwhile, cubosomes are biocompatible nanocarriers that enhance lipophilic drug delivery. Therefore, in this study, we formulated a novel SIM-loaded cubosome (SIM-CB) and analyzed its cytotoxic activity on MCF-7 cancer cells in comparison with free SIM. Methods The present study tested the cytotoxic activity of SIM-CB on MCF-7 cells, in comparison with SIM using sulphorhodamine assay. We analyzed SIM-CB effect on apoptosis and cell cycle using flowcytometry, and investigated its effect on Bcl-2, caspase 3, ROS, reduced glutathione (GSH), lipid peroxides and GPX4 enzyme. Finally, we tested the persistence of SIM-CB apoptosis and ferroptosis activities on MCF-7 cells in presence of vitamin E, a potent antioxidant and ferroptosis inhibitor. Results SIM-CB was successfully formulated at the nano size. SIM-CB significantly increased simvastatin therapeutic activity, with IC 50 of SIM-CB 52% lower than SIM. 95% CI [1.8, 2.7], SD = 0.34 for SIM-CB, and [4.1, 5.2], SD = 0.45 for SIM. Compared with free SIM, SIM-CB doubled total deaths and increased apoptosis (p < 0.05). Moreover, SIM-CB remarkably increased caspase-3, ROS, and lipid peroxide levels but decreased antiapoptotic Bcl-2 protein, GSH, and GPX4 compared with free SIM. Notably, SIM-CB elicited a high distinguished resistance against the inhibitory effects of vitamin E. Conclusion To the best of our knowledge, this study is the first to present SIM-CB as a promising means to enhancing the therapeutic potential of simvastatin against breast cancer cells, through potentiating both apoptosis and ferroptosis.
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