Synchrotron X-ray imaging reveals a correlation of tumor copper speciation with Clioquinol's anticancer activity.
Tumor development and metastasis depend on angiogenesis that requires certain growth factors, proteases, and the trace element copper (Cu). Recent studies suggest that Cu could be used as a novel target for cancer therapies. Clioquinol (CQ), an antibiotic that is able to form stable complexes with Cu or zinc (Zn), has shown proteasome-inhibitory, androgen receptor-suppressing, apoptosis-inducing, and antitumor activities in human cancer cells and xenografts. The mechanisms underlying the interaction of CQ with cellular Cu, the alteration of the Cu/Zn ratio and the antitumor role of CQ in vivo have not been fully elucidated. We report here that Cu accumulates in tumor tissue and that the Cu/Zn balances in tumor, but not normal, tissue change significantly after the treatment with CQ. Cu speciation analysis showed that the Cu(I) species is predominant in both normal and tumor tissues and that Cu(II) content was significantly increased in tumor, but not normal tissue after CQ treatment. Our findings indicate that CQ can interact with cellular Cu in vivo, dysregulates the Cu/Zn balance and is able to convert Cu(I) to Cu(II) in tumor tissue. This conversion of Cu(I) to Cu(II) may be associated with CQ-induced proteasome inhibition and growth suppression in the human prostate tumor xenografts.
Barrea
Raul A
RA
Biophysics Collaborative Access Team (BioCAT), CSRRI and Dept of Biological Chemical, and Physical Sciences, Illinois Institute of Technology, Chicago, Illinois 60616, USA. rbarrea@gmail.com
Chen
Di
D
Irving
Thomas C
TC
Dou
Q Ping
QP
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D007464:Clioquinol / Q000494:pharmacology*; D003300:Copper / Q000378:metabolism*; D003952:Diagnostic Imaging; D008297:Male; D051379:Mice; D011471:Prostatic Neoplasms / Q000378:metabolism*; D017356:Synchrotrons; D014965:X-Rays; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D003300:Copper; D007464:Clioquinol