From 2D to 3D Colorectal Cancer Patient-Derived Organoids (PDOs) and In Vivo Models: Copper(II) Complexes as Promising New Antitumor Agents.

Two copper(II) complexes, (1) [CuCl2(tmp-terpy)] and (2) {[CuCl(tmp-terpy)]·PF6}n, (tmp-terpy-4'-(3,4,5-trimethoxy-phenyl)-2,2':6',2″-terpyridine) were designed, characterized, and evaluated for cytotoxicity in 2D human cell models (HCT116, HCT116-DoxR, and in normal primary fibroblasts), and 3D colorectal cancer (CRC) spheroids and patient-derived organoids (PDOs). Both complexes demonstrated potent antiproliferative effects, alone and in combination with the FOLFOX (FF), across all 3D models. Importantly, the cytotoxic effects of complex 1 were significantly more pronounced in tumor-derived PDOs than in normal tissue-derived PDOs. Complex 1 induced reactive oxygen species (ROS) production, triggering intrinsic apoptosis and autophagy, consistent with a multimodal anticancer mechanism. It also exerted a cytostatic effect, as shown by delayed cell-cycle progression, and antiangiogenic activity in vivo without systemic toxicity. Notably, cotreatment of complex 1 with FF significantly potentiated cytotoxicity in 3D tumor spheroids and PDOs tumor-derived-PDOs. [CuCl2(tmp-terpy)] alone or in combination with the FF regimen warrants further evaluation in advanced preclinical models.