Digoxin-Mediated Inhibition of Potential Hypoxia-Related Angiogenic Repair in Modulated Electro-Hyperthermia (mEHT)-Treated Murine Triple-Negative Breast Cancer Model

Abstract

Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer type with no targeted therapy and hence limited treatment options. Modulated electrohyperthermia (mEHT) is a novel complementary therapy where a 13.56 MHz radiofrequency current targets cancer cells selectively, inducing tumor damage by thermal and electromagnetic effects. We observed severe vascular damage in mEHT-treated tumors and investigated the potential synergism between mEHT and inhibition of tumor vasculature recovery in our TNBC mouse model. 4T1/4T07 isografts were orthotopically inoculated and treated three to five times with mEHT. mEHT induced vascular damage 4−12 h after treatment, leading to tissue hypoxia detected at 24 h. Hypoxia in treated tumors induced an angiogenic recovery 24 h after the last treatment. Administration of the cardiac glycoside digoxin with the potential hypoxia-inducible factor 1-α (HIF1-α) and angiogenesis inhibitory effects could synergistically augment mEHT-mediated tumor damage and reduce tissue hypoxia signaling and consequent vascular recovery in mEHT-treated TNBC tumors. Conclusively, repeated mEHT induced vascular damage and hypoxic stress in TNBC that promoted vascular recovery. Inhibiting this hypoxic stress signaling enhanced the effectiveness of mEHT and may potentially enhance other forms of cancer treatment.

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

“…Modulated electro-hyperthermia (mEHT) is a noninvasive adjuvant cancer treatment approved for clinical use in different cancer types. − mEHT uses an amplitude-modulated, 13.56 MHz radiofrequency electromagnetic field by capacitive coupling between two electrodes surrounding the cancer. , Due to the difference in bioelectrical properties between cancerous and healthy tissues, , the electromagnetic field energy is absorbed mainly by cancer tissues, resulting in cancer-specific tissue damage. , At the cellular level, mEHT generates heat, leading to cellular stress and upregulation of HSPs . We previously demonstrated enhanced anticancer effects of mEHT by inhibiting HSP70 in vitro and heat shock factor 1 (HSF1) in vivo, utilizing the small molecule inhibitors of the heat shock response central regulator (i.e., HSF1): quercetin and KRIBB11, and by knocking down HSF1 production of the tumor cells with a CRISPR/Cas9 construct .…”