Clioquinol, a Therapeutic Agent for Alzheimer's Disease, Has Proteasome-Inhibitory, Androgen Receptor–Suppressing, Apoptosis-Inducing, and Antitumor Activities in Human Prostate Cancer Cells and Xenografts

Chen, Di; Cui, Qiuzhi Cindy; Yang, Huanjie; Barrea, Raúl A.; Sarkar, Fazlul H.; Shen, Sheng; Yan, Bing; Reddy, G. Prem Veer; Dou, Q. Ping

doi:10.1158/0008-5472.can-06-3546

Cited by 194 publications

(179 citation statements)

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“…[22][23][24][25][26][27][28][29] It has long been established that inhibition of the proteasome prevents activation of NFκB by stabilizing the phosphorylated form of IκBα that is still bound to the NFκB heterodimer, retaining it in the cytoplasm. 30 Western blot analysis of lysates prepared from cells treated with the well-described proteasome inhibitor lactacystine 31 revealed a prolonged IκBα phosphorylation following TNF induction, consistent with impaired IκBα degradation (Fig.…”

Section: Copper Blocks Nfκb Nuclear Translocationmentioning

confidence: 99%

Copper is a potent inhibitor of both the canonical and non-canonical NFκB pathways

et al. 2014

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Section: Copper Blocks Nfκb Nuclear Translocationmentioning

confidence: 99%

Copper is a potent inhibitor of both the canonical and non-canonical NFκB pathways

et al. 2014

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“…To test this, we mixed CQ and CuCl 2 in a 1:1 molar ratio and an observable color change occurred, indicating that a chemical reaction had taken place (136). This was further confirmed by the use of X-ray absorption near-edge spectroscopy (XANES) and extended X-ray absorption fine structure spectroscopy (EXAFS), which showed that the CQ-Cu mixture had a different copper oxidation state than CQ or CuCl 2 alone, which verified that a coordination complex with copper had indeed been formed (136).…”

Section: Clioquinolmentioning

confidence: 99%

New applications of old metal-binding drugs in the treatment of human cancer

Dou¹

2012

Front Biosci

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Significant advances in the use of metal complexes, precipitated by platinum, have fostered a renewed interest in harnessing their rich potential in the treatment of cancer. In addition to platinum-based complexes, the anticancer properties of other metals such as ruthenium have been realized, and ruthenium-based compounds are currently being investigated in clinical trials. Since the process of drug development can be expensive and cumbersome, finding new applications of existing drugs may provide effective means to expedite the regulatory process in bringing new drugs to the clinical setting. Encouraging findings from laboratory studies reveal significant anticancer activity from different classes of metal-chelating compounds, such as disulfiram, clioquinol, and dithiocarbamate derivatives that are currently approved for the treatment of various pathological disorders. Their use as coordination complexes with metals such as copper, zinc, and gold that target the ubiquitin-proteasome pathway have shown significant promise as potential anticancer agents. This review discusses the unique role of several selected metals in relation to their anti-cancer properties as well as the new therapeutic potential of several previously approved metal-chelating drugs. In vitro and in vivo experimental evidence along with mechanisms of action (e.g., via targeting the tumor proteasome) will also be discussed with anticipation of strengthening this exciting new concept. KeywordsDisulfiram; Clioquinol; Dithiocarbamates; Copper; Zinc; Ubiquitin-Proteasome Pathway; Proteasome Inhibitor; Chymotrypsin-Like Activity; Review INTRODUCTION The use of metal complexes for cancer treatmentThe development of metal-based complexes for the treatment of cancer began with the discovery of the anti-cancer properties of cisplatin in the early 1960s (Figure 1). Over 90% of testicular cancer cases have been cured by cisplatin, and it has also been important in the treatment of several other types of cancer, including ovarian, cervical, bladder, head and neck, melanoma, and lymphomas (1). Cisplatin interacts with DNA and forms adducts which interfere with the replication and transcription processes, and ultimately triggers apoptosis (2). These cisplatin-DNA interactions have been extensively studied, and it has been clearly shown that a (Pt)-GG intrastrand cross-link is responsible for the cytotoxicity of Send correspondence to: Qing Ping Dou, The Developmental Therapeutics Program, Barbara Ann Karmanos Cancer Institute, and Departments of Oncology, Pharmacology and Pathology, School of Medicine, Wayne State University, Detroit, Michigan 48201, USA, doup@karmanos.org. NIH Public Access Author ManuscriptFront Biosci (Schol Ed). Author manuscript; available in PMC 2013 May 07. Published in final edited form as:Front Biosci (Schol Ed). ; 4: 375-391. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript cisplatin (3). However, the toxicities associated with cisplatin, coupled with intrinsic and acquired drug resistance, ha...

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“…CQ-Cu (1:1 ratio) inhibits purified 20S proteasome (IC 50 =2.5 µM), as well as intact cellular proteasome in C4-2B and LNCaP prostate cancer cells. In addition to inhibition of proteasomal activity, CQ-Cu suppressed androgen receptor expression, inhibited cellular proliferation and induced apoptosis in these cells [28]. In C4-2B xenograft-bearing mice, tumour growth was significantly suppressed (66%) following CQ treatment, and proteasome inhibition was also evident [28].…”

mentioning

confidence: 99%

“…Clioquinol (5-chloro-7-iodo-8-hydroxyquinoline, CQ), is a lipophilic compound that is currently used to treat Alzheimer's and Huntington's diseases [27] and is able to form stable complexes with copper(II) [28]. CQ-Cu (1:1 ratio) inhibits purified 20S proteasome (IC 50 =2.5 µM), as well as intact cellular proteasome in C4-2B and LNCaP prostate cancer cells.…”

mentioning

confidence: 99%

“…In addition to inhibition of proteasomal activity, CQ-Cu suppressed androgen receptor expression, inhibited cellular proliferation and induced apoptosis in these cells [28]. In C4-2B xenograft-bearing mice, tumour growth was significantly suppressed (66%) following CQ treatment, and proteasome inhibition was also evident [28]. Another copper-binding compound, disulfiram (tetraethylthiuram disulfide, DSF) was also tested for its potential as a proteasome inhibitor [29].…”

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