Therapeutic Potential of 2,2′:6′,2″-Terpyridine-Based Au(III), Pt(II), and Mn(II) Complexes against 2D and 3D Human Colorectal Resistant Cancer Cells

The antiproliferative effect of [AuCl(tmp-terpy)](PF6)2 (1), [PtCl(tmp-terpy)](CF3SO3) (2), [MnCl2(tmp-terpy)] (3), and 4′-(3,4,5-trimethoxy-phenyl)-2,2′:6′,2″-terpyridine (tmp-terpy) was analyzed in sensitive and doxorubicin-resistant (DoxR) colorectal cancer (CRC) cell lines and in normal primary human fibroblasts. Comprehensive studies were performed for 1 and tmp-terpy, showing the strongest cytotoxicity in HCT116DoxR 2D cells and having the capability to induce the loss of cell viability in 3D HCT116DoxR spheroids. Complex 1 internalizes CRC-resistant cancer cells and increases the number of reactive oxygen species (ROS), triggering cell death by apoptosis and autophagy. Changes in protein expression levels of HCT116DoxR cells exposed to 1 and tmp-terpy primarily affect protein folding, apoptosis, and stress response, consistent with the observed induction of programmed cell death and ROS. The combination of 1 or tmp-terpy with oxaliplatin (OX) and cisplatin (Cis) shows cytotoxic effects in 3D CRC-resistant spheroids. No in vivo toxicity in a chicken embryo is observed, even when 1 is combined with an OX and Cis.