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

• Main Authors: Ng, Chew Hee, Kong, Siew Ming, Tiong, Yee Lian, Maah, Mohd Jamil, Sukram, Nurhazwani, Ahmad, Munirah, Khoo, Alan Soo Beng
• Format: Journal Article
• Language: English
• Published: 26-03-2014
• ISSN: 1756-5901; 1756-591X
• DOI: 10.1039/c3mt00276d

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.