caa a22 4500 605506949 CHVBK 20210128100629.0 cr unu---uuuuu 210128e20150101xx s 000 0 eng 10.1007/s00775-014-1219-1 doi (NATIONALLICENCE)springer-10.1007/s00775-014-1219-1 l -Ornithine Schiff base-copper and -cadmium complexes as new proteasome inhibitors and apoptosis inducers in human cancer cells [Elektronische Daten] [Zhongyu Zhang, Caifeng Bi, Yuhua Fan, Nan Zhang, Rahul Deshmukh, Xingchen Yan, Xiuwen Lv, Pengfei Zhang, Xia Zhang, Q. Dou] 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. Graphical Abstract: SBIC, 2014 Proteasome inhibitors nationallicence Apoptosis nationallicence Copper nationallicence Cadmium nationallicence Metal-based anticancer drugs nationallicence DMSO : Dimethyl sulfoxide nationallicence MTT : 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide nationallicence PARP : Poly(ADP-ribose) polymerase nationallicence PBS : Phosphate-buffered saline nationallicence Suc-LLVY-AMC : N-Succinyl-Leu-Leu-Val-Tyr-7-amino-4-methylcoumarin nationallicence UPS : Ubiquitin-proteasome system nationallicence Zhang Zhongyu Key Laboratory of Marine Chemistry Theory and Technology, Ministry of Education, College of Chemistry and Chemical Engineering, Ocean University of China, 238 Songling Road, 266100, Qingdao, Shandong, China aut Bi Caifeng Key Laboratory of Marine Chemistry Theory and Technology, Ministry of Education, College of Chemistry and Chemical Engineering, Ocean University of China, 238 Songling Road, 266100, Qingdao, Shandong, China aut Fan Yuhua Key Laboratory of Marine Chemistry Theory and Technology, Ministry of Education, College of Chemistry and Chemical Engineering, Ocean University of China, 238 Songling Road, 266100, Qingdao, Shandong, China aut Zhang Nan Key Laboratory of Marine Chemistry Theory and Technology, Ministry of Education, College of Chemistry and Chemical Engineering, Ocean University of China, 238 Songling Road, 266100, Qingdao, Shandong, China aut Deshmukh Rahul Department of Oncology, Pharmacology and Pathology, Barbara Ann Karmanos Cancer Institute, School of Medicine, Wayne State University, 540.1 HWCRC, 4100 John R Road, 48201, Detroit, MI, USA aut Yan Xingchen Key Laboratory of Marine Chemistry Theory and Technology, Ministry of Education, College of Chemistry and Chemical Engineering, Ocean University of China, 238 Songling Road, 266100, Qingdao, Shandong, China aut Lv Xiuwen Key Laboratory of Marine Chemistry Theory and Technology, Ministry of Education, College of Chemistry and Chemical Engineering, Ocean University of China, 238 Songling Road, 266100, Qingdao, Shandong, China aut Zhang Pengfei Key Laboratory of Marine Chemistry Theory and Technology, Ministry of Education, College of Chemistry and Chemical Engineering, Ocean University of China, 238 Songling Road, 266100, Qingdao, Shandong, China aut Zhang Xia Key Laboratory of Marine Chemistry Theory and Technology, Ministry of Education, College of Chemistry and Chemical Engineering, Ocean University of China, 238 Songling Road, 266100, Qingdao, Shandong, China aut Dou Q. Department of Oncology, Pharmacology and Pathology, Barbara Ann Karmanos Cancer Institute, School of Medicine, Wayne State University, 540.1 HWCRC, 4100 John R Road, 48201, Detroit, MI, USA aut JBIC Journal of Biological Inorganic Chemistry Springer Berlin Heidelberg 20/1(2015-01-01), 109-121 0949-8257 20:1<109 2015 20 775 https://doi.org/10.1007/s00775-014-1219-1 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00775-014-1219-1 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Zhang Zhongyu Key Laboratory of Marine Chemistry Theory and Technology, Ministry of Education, College of Chemistry and Chemical Engineering, Ocean University of China, 238 Songling Road, 266100, Qingdao, Shandong, China aut NATIONALLICENCE 700 1- Bi Caifeng Key Laboratory of Marine Chemistry Theory and Technology, Ministry of Education, College of Chemistry and Chemical Engineering, Ocean University of China, 238 Songling Road, 266100, Qingdao, Shandong, China aut NATIONALLICENCE 700 1- Fan Yuhua Key Laboratory of Marine Chemistry Theory and Technology, Ministry of Education, College of Chemistry and Chemical Engineering, Ocean University of China, 238 Songling Road, 266100, Qingdao, Shandong, China aut NATIONALLICENCE 700 1- Zhang Nan Key Laboratory of Marine Chemistry Theory and Technology, Ministry of Education, College of Chemistry and Chemical Engineering, Ocean University of China, 238 Songling Road, 266100, Qingdao, Shandong, China aut NATIONALLICENCE 700 1- Deshmukh Rahul Department of Oncology, Pharmacology and Pathology, Barbara Ann Karmanos Cancer Institute, School of Medicine, Wayne State University, 540.1 HWCRC, 4100 John R Road, 48201, Detroit, MI, USA aut NATIONALLICENCE 700 1- Yan Xingchen Key Laboratory of Marine Chemistry Theory and Technology, Ministry of Education, College of Chemistry and Chemical Engineering, Ocean University of China, 238 Songling Road, 266100, Qingdao, Shandong, China aut NATIONALLICENCE 700 1- Lv Xiuwen Key Laboratory of Marine Chemistry Theory and Technology, Ministry of Education, College of Chemistry and Chemical Engineering, Ocean University of China, 238 Songling Road, 266100, Qingdao, Shandong, China aut NATIONALLICENCE 700 1- Zhang Pengfei Key Laboratory of Marine Chemistry Theory and Technology, Ministry of Education, College of Chemistry and Chemical Engineering, Ocean University of China, 238 Songling Road, 266100, Qingdao, Shandong, China aut NATIONALLICENCE 700 1- Zhang Xia Key Laboratory of Marine Chemistry Theory and Technology, Ministry of Education, College of Chemistry and Chemical Engineering, Ocean University of China, 238 Songling Road, 266100, Qingdao, Shandong, China aut NATIONALLICENCE 700 1- Dou Q. Department of Oncology, Pharmacology and Pathology, Barbara Ann Karmanos Cancer Institute, School of Medicine, Wayne State University, 540.1 HWCRC, 4100 John R Road, 48201, Detroit, MI, USA aut NATIONALLICENCE 773 0- JBIC Journal of Biological Inorganic Chemistry Springer Berlin Heidelberg 20/1(2015-01-01), 109-121 0949-8257 20:1<109 2015 20 775