1,10-Phenanthroline promotes copper complexes into tumor cells and induces apoptosis by inhibiting the proteasome activity

• Published in: Journal of biological inorganic chemistry Vol. 17; no. 8; pp. 1257 - 1267
• Main Authors: Zhang, Zhen, Bi, Caifeng, Schmitt, Sara M., Fan, Yuhua, Dong, Lili, Zuo, Jian, Dou, Q. Ping
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.12.2012
• Subjects: Apoptosis - drug effects; Biochemistry; Biomedical and Life Sciences; Blotting, Western; Cell Line, Tumor; Cell Proliferation - drug effects; Coordination Complexes - chemical synthesis; Coordination Complexes - chemistry; Coordination Complexes - pharmacology; Coordination Complexes - therapeutic use; Copper - chemistry; Dose-Response Relationship, Drug; Female; Humans; Life Sciences; Male; Microbiology; Molecular Structure; Neoplasms - drug therapy; Original Paper; Phenanthrolines - chemistry; Phenanthrolines - pharmacology; Proteasome Inhibitors - chemical synthesis; Proteasome Inhibitors - chemistry; Proteasome Inhibitors - pharmacology; Proteasome Inhibitors - therapeutic use; 1,10-Phenanthroline; Indole-3-propionic acid; Indole-3-acetic acid; Copper; Apoptosis
• ISSN: 0949-8257; 1432-1327
• DOI: 10.1007/s00775-012-0940-x

Indole-3-acetic acid and indole-3-propionic acid, two potent natural plant growth hormones, have attracted attention as promising prodrugs in cancer therapy. Copper is known to be a cofactor essential for tumor angiogenesis. We have previously reported that taurine, l -glutamine, and quinoline-2-carboxaldehyde Schiff base copper complexes inhibit cell proliferation and proteasome activity in human cancer cells. In the current study, we synthesized two types of copper complexes, dinuclear complexes and ternary complexes, to investigate whether a certain structure could easily carry copper into cancer cells and consequently inhibit tumor proteasome activity and induce apoptosis. We observed that ternary complexes binding with 1,10-phenanthroline are more potent proteasome inhibitors and apoptosis inducers than dinuclear complexes in PC-3 human prostate cancer cells. Furthermore, the ternary complexes potently inhibit proteasome activity before induction of apoptosis in MDA-MB-231 human breast cancer cells, but not in nontumorigenic MCF-10A cells. Our results suggest that copper complexes binding with 1,10-phenanthroline as the third ligand could serve as potent, selective proteasome inhibitors and apoptosis inducers in tumor cells, and that the ternary complexes may be good potential anticancer drugs.