Circumventing Drug Resistance in Colorectal Cancer Cells with Novel Platinum(II) Complexes with Terpyridine Derivatives
Anna M. Maroń, Sandra Cordeiro, Cristiana Marques, Rita Sequeira, Beatriz Salas, André Luz, Katarzyna Choroba, Bartosz Zowiślok, Sławomir Kula, Barbara Machura, Pedro V. Baptista, Alexandra R. FernandesAbstract
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.