Tumor cellular proteasome inhibition and growth suppression by 8-hydroxyquinoline and clioquinol requires their capabilities to bind copper and transport copper into cells.
We have previously reported that when mixed with copper, 8-hydroxyquinoline (8-OHQ) and its analog clioquinol (CQ) inhibited the proteasomal activity and proliferation in cultured human cancer cells. CQ treatment of high-copper-containing human tumor xenografts also caused cancer suppression, associated with proteasome inhibition in vivo. However, the nature of the copper dependence of these events has not been elucidated experimentally. In the current study, using chemical probe molecules that mimic the structures of 8-OHQ and CQ, but have no copper-binding capability, we dissected the complex cellular processes elicited by 8-OHQ-Cu and CQ-Cu mixtures and revealed that copper binding to 8-OHQ or CQ is required for transportation of the copper complex into human breast cancer cells and the consequent proteasome-inhibitory, growth-suppressive, and apoptosis-inducing activities. In contrast, the non-copper-binding analogs of 8-OHQ or CQ blocked the very first step-copper binding-in this chain of events mediated by 8-OHQ-Cu or CQ-Cu.
Zhai
Shumei
S
School of Chemistry and Chemical Engineering, Shandong University, Jinan, China.
Yang
Lei
L
Cui
Qiuzhi Cindy
QC
Sun
Ying
Y
Dou
Q Ping
QP
Yan
Bing
B
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D007464:Clioquinol / Q000378:metabolism / Q000494:pharmacology*; D003300:Copper / Q000378:metabolism*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015125:Oxyquinoline / Q000378:metabolism / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D061988:Proteasome Inhibitors; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D015125:Oxyquinoline; D003300:Copper; D007464:Clioquinol