Synergistic Therapeutic Effects of Zn Ions and Pimozide in Breast Cancer Cells.

Zinc (Zn) ions play a crucial role in cancer therapy due to their ability to induce reactive oxygen species (ROS) generation, oxidative stress, and ferroptosis. Combining Zn ions with other therapeutic agents can significantly enhance their efficacy through synergistic mechanisms. This study explores the synergistic mechanism of Zn ions from pH-responsive ZIF-8 and repurposed drug pimozide in tumor microenvironment mimic conditions. The synthesized ZIF-8 exhibited an average size distribution of 36 nm with 52.21 ± 1.86% encapsulation efficiency for pimozide. Notably, the maximum drug release of 84.13% was observed at pH 6. Furthermore, in vitro cytotoxicity investigations revealed heightened efficacy of pimozide-ZIF-8 formulations after 48 h of treatment. In addition, pimozide-ZIF-8 concomitantly induced ferroptosis and apoptosis in MCF-7 cells at pH 6, underscoring the pharmacological potency of the composite structure. Complementary to these experimental findings, an in silico network analysis was performed to uncover protein interaction networks of Zn ions and pimozide, highlighting their multi-targeted action in cancer-related pathways. Altogether, this dual-action approach activates both ferroptosis and apoptosis, presenting a promising therapeutic strategy for breast cancer that offers enhanced efficacy and targeting through the combined effects of Zn ions and pimozide.