l-Ornithine Schiff base–copper and –cadmium complexes as new proteasome inhibitors and apoptosis inducers in human cancer cells

• DOI: 10.1007/s00775-014-1219-1
• Publication Date: 2014-12-02T12:41:16Z
• Authors: Zhongyu Zhang; Caifeng Bi; Yuhua Fan; Nan Zhang; Rahul Deshmukh; Xingchen Yan; Xiuwen Lv; Pengfei Zhang; Xia Zhang; Q. Ping Dou
• Keywords: Ornithine; 0301 basic medicine; Proteasome Endopeptidase Complex; Antineoplastic Agents; Apoptosis; 3. Good health; Inhibitory Concentration 50; 03 medical and health sciences; Coordination Complexes; Cell Line, Tumor; Humans; Drug Screening Assays, Antitumor; Proteasome Inhibitors; Copper; Schiff Bases; Cadmium; Cell Proliferation

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.