title: L-Ornithine Schiff base-copper and -cadmium complexes as new proteasome inhibitors and apoptosis inducers in human cancer cells.
abstract: Ubiquitin-proteasome system (UPS) plays a crucial role in many cellular processes such as cell cycle, proliferation and apoptosis. Aberrant activation of UPS may result in cellular transformation or other altered pathological conditions. Previous studies have shown that metal-based complexes could inhibit proteasome activity and induce apoptosis in certain human cancer cells. In the current study, we report that the cadmium and copper complexes with heterocycle-ornithine Schiff base are potent inhibitors of proteasomal chymotrypsin-like (CT-like) activity, leading to induction of apoptosis in cancer cells. Two novel copper-containing complexes and two novel cadmium-containing complexes with different heterocycle-ornithine Schiff base structures as ligands were synthesized and characterized. We found that complexes Cu1, Cd1 and Cd2 show proteasome-inhibitory activities in human breast cancer MDA-MB-231 and human prostate cancer LNCaP cells, resulting in the accumulation of p27, a natural proteasome substrate and other ubiquitinated proteins, followed by the induction of apoptosis. Our results suggest that metal complexes with heterocycle-ornithine Schiff base have proteasome-inhibitory capabilities and have the potential to be developed into novel anticancer drugs.
authors.affiliation: Key Laboratory of Marine Chemistry Theory and Technology, Ministry of Education, College of Chemistry and Chemical Engineering, Ocean University of China, 238 Songling Road, Qingdao, 266100, Shandong, China.|Department of Oncology, Pharmacology and Pathology, Barbara Ann Karmanos Cancer Institute, School of Medicine, Wayne State University, 540.1 HWCRC, 4100 John R Road, Detroit, MI, 48201, USA.
authors.forename: Zhongyu
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Marine Chemistry Theory and Technology, Ministry of Education, College of Chemistry and Chemical Engineering, Ocean University of China, 238 Songling Road, Qingdao, 266100, Shandong, China. bicaifeng301@163.com.
authors.forename: Caifeng
authors.initials: C
authors.lastname: Bi
authors.affiliation: Key Laboratory of Marine Chemistry Theory and Technology, Ministry of Education, College of Chemistry and Chemical Engineering, Ocean University of China, 238 Songling Road, Qingdao, 266100, Shandong, China.
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Key Laboratory of Marine Chemistry Theory and Technology, Ministry of Education, College of Chemistry and Chemical Engineering, Ocean University of China, 238 Songling Road, Qingdao, 266100, Shandong, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Department of Oncology, Pharmacology and Pathology, Barbara Ann Karmanos Cancer Institute, School of Medicine, Wayne State University, 540.1 HWCRC, 4100 John R Road, Detroit, MI, 48201, USA.
authors.forename: Rahul
authors.initials: R
authors.lastname: Deshmukh
authors.affiliation: Key Laboratory of Marine Chemistry Theory and Technology, Ministry of Education, College of Chemistry and Chemical Engineering, Ocean University of China, 238 Songling Road, Qingdao, 266100, Shandong, China.
authors.forename: Xingchen
authors.initials: X
authors.lastname: Yan
authors.affiliation: Key Laboratory of Marine Chemistry Theory and Technology, Ministry of Education, College of Chemistry and Chemical Engineering, Ocean University of China, 238 Songling Road, Qingdao, 266100, Shandong, China.
authors.forename: Xiuwen
authors.initials: X
authors.lastname: Lv
authors.affiliation: Key Laboratory of Marine Chemistry Theory and Technology, Ministry of Education, College of Chemistry and Chemical Engineering, Ocean University of China, 238 Songling Road, Qingdao, 266100, Shandong, China.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Marine Chemistry Theory and Technology, Ministry of Education, College of Chemistry and Chemical Engineering, Ocean University of China, 238 Songling Road, Qingdao, 266100, Shandong, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Oncology, Pharmacology and Pathology, Barbara Ann Karmanos Cancer Institute, School of Medicine, Wayne State University, 540.1 HWCRC, 4100 John R Road, Detroit, MI, 48201, USA. doup@karmanos.org.
authors.forename: Q Ping
authors.initials: QP
authors.lastname: Dou
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002104:Cadmium / Q000737:chemistry; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056831:Coordination Complexes / Q000737:chemistry / Q000494:pharmacology*; D003300:Copper / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020128:Inhibitory Concentration 50; D009952:Ornithine / Q000737:chemistry; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry; D061988:Proteasome Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D012545:Schiff Bases
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D061988:Proteasome Inhibitors; D012545:Schiff Bases; D002104:Cadmium; D003300:Copper; D009952:Ornithine; D046988:Proteasome Endopeptidase Complex