Ivermectin Synergizes with Modulated Electro-hyperthermia and Improves Its Anticancer Effects in a Triple-Negative Breast Cancer Mouse Model

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, with limited treatment options. Modulated electro-hyperthermia (mEHT) is a novel adjuvant cancer therapy that induces selective cancer damage. However, mEHT upregulates heat shock protein beta 1 (HSPB1), a cancer-promoting stress chaperone molecule. Thus, we investigated whether ivermectin (IVM), an anthelmintic drug, may synergize with mEHT and enhance its anticancer effects by inhibiting HSPB1 phosphorylation. Isogenic 4T1 TNBC cells were inoculated into BALB/c mice and treated with mEHT, IVM, or a combination of both. IVM synergistically improved the tumor growth inhibition achieved by mEHT. Moreover, IVM downregulated mEHT-induced HSPB1 phosphorylation. Thus, the strongest cancer tissue damage was observed in the mEHT + IVM-treated tumors, coupled with the strongest apoptosis induction and proliferation inhibition. In addition, there was no significant body weight loss in mice treated with mEHT and IVM, indicating that this combination was well-tolerated. In conclusion, mEHT combined with IVM is a new, effective, and safe option for the treatment of TNBC.