Circumventing Drug Resistance in Colorectal Cancer Cells with Novel Platinum(II) Complexes with Terpyridine Derivatives

Abstract Colorectal cancer (CRC) remains a major global health burden, with approximately 2 million new cases and 1 million deaths annually. The growing resistance to conventional chemotherapy highlights the need for new therapeutic strategies against drug-resistant CRC. In this study, platinum(II) complexes of the general formula [PtCl(Ln)]CF3SO3, based on substituted 2,2′:6′,2″-terpyridines (Pt1) and 2,6-bis(thiazol-2-yl)pyridines (Pt2), were synthesized and evaluated for anticancer activity. Their antiproliferative effects were assessed in doxorubicin-sensitive and doxorubicin-resistant CRC cell lines, as well as primary dermal fibroblasts. Among the tested complexes, Pt1a showed the highest potency, exhibiting strong cytotoxicity against HCT116-DoxR cells (IC50 = 0.7 μM). Mechanistic studies revealed that Pt1a increases reactive oxygen species levels, binds DNA, disrupts cell cycle progression, and induces apoptosis and autophagy. Pt1a also displayed anti-metastatic and anti-angiogenic activities, showed favourable interaction with bovine serum albumin, and exhibited no detectable toxicity in a chicken embryo model.