Clioquinol independently targets NF-kappaB and lysosome pathways in human cancer cells.
We have reported that clioquinol alters lysosome integrity, inhibits nuclear factor kappa B (NF-kappaB) activity, and induces apoptosis in human cancer cells. The present study investigated whether clioquinol targets both pathways dependently or independently in human prostate cancer DU 145 cells. Clioquinol inhibited NF-kappaB activity, an effect being more pronounced in the presence of zinc. This inhibition was mediated through a reduced nuclear level of p65, the most frequently detected NF-kappaB subunit. Clioquinol also induced alterations of lysosome permeability in a zinc concentration-dependent manner. Pretreatment of the cells with ammonium, a lysosome protection agent, attenuated clioquinol-induced disruption of the lysosomes, yet ammonium had no effect on clioquinol-induced inhibition of NF-kappaB signaling. MG132, an established NF-kappaB inhibitor, suppressed NF-kappaB activity without causing alterations of lysosome permeability. These findings indicate that clioquinol targets NF-kappaB and lysosome pathways independently, favoring further development of clioquinol as a novel anticancer agent.
Yu
Haijun
H
Department of Radio-Chemotherapy, Zhongnan Hospital, Wuhan University, Wuhan, China.
Lou
Jessica R
JR
Ding
Wei-Qun
WQ
D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects; D007464:Clioquinol / Q000494:pharmacology*; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008247:Lysosomes / Q000187:drug effects*; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D061988:Proteasome Inhibitors; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D015032:Zinc / Q000494:pharmacology
D000970:Antineoplastic Agents; D007976:Leupeptins; D016328:NF-kappa B; D061988:Proteasome Inhibitors; D000644:Quaternary Ammonium Compounds; D007464:Clioquinol; D046988:Proteasome Endopeptidase Complex; D015032:Zinc; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde