Anticancer activity and computational modeling of ternary copper (II) complexes with 3-indolecarboxylic acid and 1,10-phenanthroline.
Metal-containing compounds have been extensively studied for many years as potent proteasome inhibitors. The 20S proteasome, the main component of the ubiquitin proteasome pathway, is one of the excellent targets in anticancer drug development. We recently reported that several copper complexes were able to inhibit cancer-special proteasome and induce cell death in human cancer cells. However, the involved molecular mechanism is not known yet. We therefore synthesized three copper complexes and investigated their abilities on inhibiting proteasome activity and inducting apoptosis in human breast cancer cells. Furthermore, we employed molecular dockings to analyze the possible interaction between the synthetic copper complexes and the β5 subunit of proteasome which only reflects the chymotrypsin-like activity. Our results demonstrate that three Cu(II) complexes possess potent proteasome inhibition capability in a dose-dependent and time-dependent manner in MDA-MB-231 human breast cancer cells. They could bind to the β5 subunit of the 20S proteasome, which consequently cause deactivation of the proteasome and tumor cell death. The present study is significant for providing important theoretical basis for design and synthesis of anticancer drugs with low toxicity, high efficiency and high selectivity.
School of Pharmacy, Jining Medical University, Rizhao, Shandong 276800, P.R. China.
Zhen
Z
Zhang
School of Pharmacy, Jining Medical University, Rizhao, Shandong 276800, P.R. China.
Huiyun
H
Wang
School of Pharmacy, Jining Medical University, Rizhao, Shandong 276800, P.R. China.
Qibao
Q
Wang
School of Pharmacy, Jining Medical University, Rizhao, Shandong 276800, P.R. China.
Maocai
M
Yan
School of Pharmacy, Jining Medical University, Rizhao, Shandong 276800, P.R. China.
Huannan
H
Wang
Key Laboratory of Marine Chemistry Theory and Technology, Ministry of Education, College of Chemistry and Chemical Engineering, Ocean University of China, Qingdao, Shandong 266100, P.R. China.
Caifeng
C
Bi
School of Pharmacy, Jining Medical University, Rizhao, Shandong 276800, P.R. China.
Shanshan
S
Sun
Key Laboratory of Marine Chemistry Theory and Technology, Ministry of Education, College of Chemistry and Chemical Engineering, Ocean University of China, Qingdao, Shandong 266100, P.R. China.
Yuhua
Y
Fan
D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003300:Copper / Q000008:administration & dosage* / Q000737:chemistry; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage*; D010618:Phenanthrolines / Q000008:administration & dosage* / Q000737:chemistry; D061988:Proteasome Inhibitors / Q000008:administration & dosage
C000616673:3-indolecarboxylic acid; D007211:Indoles; D010618:Phenanthrolines; D061988:Proteasome Inhibitors; D003300:Copper; C025205:1,10-phenanthroline