title: Novel 8-hydroxylquinoline analogs induce copper-dependent proteasome inhibition and cell death in human breast cancer cells.
abstract: An elevated level of copper (Cu), which is necessary for the growth and metastasis of tumor cells, has been found in many types of cancer, including breast, prostate, lung and brain. Although its molecular basis is unclear, this tumor-specific Cu elevation has been proposed to be a novel target for developing selective anti-cancer therapies. We previously reported that 8-hydroxylquinoline (8-OHQ) is able to form a Cu complex that inhibits the proteasome and induces apoptosis in cultured cancer cells. Toward the goal of discovering novel 8-OHQ analogs as potential anti-copper and anti-cancer drugs, in the current study we synthesized several 8-OHQ analogs and their copper complexes and evaluated their biological activities in human breast cancer cells. We report that when substitutions are made on the hydroxyl group of 8-OHQ, their copper mixtures have profound effects on the proteasome-inhibitory and apoptosis-inducing abilities in breast cancer MDA-MB-231 cells. In addition, the proteasome-inhibitory and apoptosis-inducing activities of 8-OHQ analog-copper mixtures are determined by both the polarity and position of the substituents. Finally, a synthetic complex of 8-OHQ analog-copper was able to inhibit the proteasome activity, induce cell death and suppress the growth selectively in breast cancer MDA-MB-231 cells, but not in normal immortalized human breast MCF-10A cells. Our results support the concept that human cancer cells and tissues, which contain an elevated copper level and are highly dependent on proteasome activity for their survival, should be sensitive to treatment with anti-copper drugs such as the novel 8-OHQ analogs described here.
authors.affiliation: The Prevention Program, Barbara Ann Karmanos Cancer Institute, and Department of Pathology, School of Medicine, Wayne State University, Detroit, MI 48201-2013, USA.
authors.forename: Vesna
authors.initials: V
authors.lastname: Milacic
authors.forename: Peifu
authors.initials: P
authors.lastname: Jiao
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Bing
authors.initials: B
authors.lastname: Yan
authors.forename: Q Ping
authors.initials: QP
authors.lastname: Dou
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D003300:Copper / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D006801:Humans; D006912:Hydroxyquinolines / Q000737:chemistry / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D006912:Hydroxyquinolines; D003300:Copper; D046988:Proteasome Endopeptidase Complex