title: Selective anticancer copper(II)-mixed ligand complexes: targeting of ROS and proteasomes.
abstract: 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)(H2O)]NO3·xH2O 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 IC50 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.
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, International Medical University, Bukit Jalil, 57000 Kuala Lumpur, Malaysia. NgChewHee@imu.edu.my.
authors.forename: Chew Hee
authors.initials: CH
authors.lastname: Ng
authors.forename: Siew Ming
authors.initials: SM
authors.lastname: Kong
authors.forename: Yee Lian
authors.initials: YL
authors.lastname: Tiong
authors.forename: Mohd Jamil
authors.initials: MJ
authors.lastname: Maah
authors.forename: Nurhazwani
authors.initials: N
authors.lastname: Sukram
authors.forename: Munirah
authors.initials: M
authors.lastname: Ahmad
authors.forename: Alan Soo Beng
authors.initials: AS
authors.lastname: Khoo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000737:chemistry / Q000494:pharmacology*; D003300:Copper / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D061988:Proteasome Inhibitors; D017382:Reactive Oxygen Species; D003300:Copper; D046988:Proteasome Endopeptidase Complex