Selective anticancer copper(ii)-mixed ligand complexes: targeting of ROS and proteasomesElectronic supplementary information (ESI) available: (i) Morphological observations of MDA-MB-231 and MCF10A cells which are untreated or treated with various concentrations of copper(ii) compounds for 24 h (Fig. S1.1-S1.5A and B); (ii) a comparison between untreated and treated MDA-MB-231 and MCF10A cells in the percentage of apoptosis after incubation with 5 μM copper(ii) complexes for 24 h by flow cytomet

Copper compounds can be alternatives to platinum-based anticancer drugs. This study investigated the effects of a series of ternary copper( ii ) complexes, [Cu(phen)(aa)(H 2 O)]NO 3 · x H 2 O 1-4 (phen = 1,10-phenanthroline; aa = gly ( 1 ), DL-ala ( 2 ), sar ( 3 ), C-dmg ( 4 )), on metastatic and cisplatin-resistant MDA-MB-231 breast cancer cells and MCF10A non-cancerous breast cells, and some aspects of the mechanisms. These complexes were distinctively more antiproliferative towards and induced greater apoptotic cell death in MDA-MB-231 than in MCF10A cells. 2 and 4 could induce cell cycle arrest only in cancer cells. Further evidence from DCFH-DA assay showed higher induction of reactive oxygen species (ROS) in treated cancer cells but minimal ROS increase in normal cells. DNA double-strand breaks, via a γ-H2AX assay, were only detected in cancer cells treated with 5 μM of the complexes. These complexes poorly inhibited chymotrypsin-like activity in the 20S rabbit proteasome while they did not inhibit the three proteolytic sites of MDA-MB-231 cells at 10 μM. However, the complexes could inhibit degradation of ubiquinated proteins of MDA-MB-231 cells. In addition, compound 4 was found to be effective against cervical (Hela), ovarian (SKOV3), lung (A549, PC9), NPC (Hone1, HK1, C666-1), breast (MCF7, T47D), lymphoma and leukemia (Nalmawa, HL60) and colorectal (SW480, SW48, HCT118) cancer cell lines with IC 50 values (24 h) in the 1.7-19.0 μM range. Single dose NCI60 screening of 4 showed the complex to be highly cytotoxic to most cancer cell types and more effective than cisplatin. The ternary copper( ii ) complexes 1-4 exhibited anticancer selectivity, as evidenced by MTT assay, % apoptosis, cell cycle arrest, ROS induction and DNA DSBs. Proteasome of cancer cells are also inhibited.