Copper(II) Complexes of Pyrazino [2,3-F][1,10]Phenanthroline Induce Cuprotosis and Immunogenic Cell Death in Triple-Negative Breast Cancer

Recently, cuproptosis has garnered tremendous attention in the field of cancer therapy. However, its effectiveness remains limited by the inadequate delivery efficiency of copper ion carriers. In this regard, we have synthesized and characterized four copper(II) complexes of pyrazino [2,3-f][1,10]phenanthroline. They demonstrated significant inhibitory effects on the proliferation of the selected cell lines. In particular, 4 exhibited more prominent inhibitory effects on the growth of TNBC cells CAL-51, MDA-MB-231, and MDA-MB-468, with IC₅₀ concentrations ranging from 0.52 to 1.56 μM. It disrupted mitochondrial function in tumor cells, promoted the aggregation of DLAT, and decreased the expression levels of the key proteins FDX1, DLAT, and LIAS involved in cuproptosis. Notably, 4 not only induces cuproptosis but also triggers immunogenic cell death, often marked by the release of damage-associated molecular patterns (DAMPs), such as calreticulin (CRT) and high mobility group box 1 protein (HMGB1). Our study offers a promising approach for cancer therapy based on cuproptosis.