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Old 06-23-2011, 09:03 PM   #1
Rich66
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Clioquinol (antibiotic, chelator)

Cancer Res. 2005 Apr 15;65(8):3389-95.
Anticancer activity of the antibiotic clioquinol.

Ding WQ, Liu B, Vaught JL, Yamauchi H, Lind SE.

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Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA. weiqun-ding@ouhsc.edu

Abstract

Clioquinol, a metal chelator, has been used for many years as an antimicrobial agent and more recently as a potential treatment for Alzheimer's disease. Because it binds copper and zinc, metals essential for the activity of the enzyme superoxide dismutase-1 (SOD1), a potential target for anticancer drug development, we investigated its effects on human cancer cells. Treatment with clioquinol reduced the viability of eight different human cancer cell lines in a concentration-dependent manner, with IC(50) values in the low micromolar range. Biochemical analysis revealed that clioquinol induced cancer cell death through apoptotic pathways that require caspase activity. Although clioquinol induced modest inhibition of SOD1 activity in treated cells, comparable inhibition by a known SOD1 inhibitor, diethyldithiocarbamate, did not result in cytotoxicity. The addition of copper, iron, or zinc did not rescue cells from cliquinol-induced cytotoxicity but enhanced its killing, arguing against metal chelation as its major mechanism of action. To test if clioquinol might act as an ionophore, a fluorescent probe was used to monitor intracellular zinc concentrations. The addition of clioquinol resulted in elevated levels of intracellular zinc, indicating that clioquinol acts as a zinc ionophore. In an in vivo xenografts mouse model, clioquinol inhibited tumor growth of xenografts over a 6-week period, without inducing visible toxicity. Our results show that clioquinol has anticancer effects both in vitro and in vivo. Transition metal ionophores may be a subclass of metal chelators with anticancer activity deserving of further development.

PMID:
15833873


Biochem J. 2009 Jan 1;417(1):133-9.
Clioquinol targets zinc to lysosomes in human cancer cells.

Yu H, Zhou Y, Lind SE, Ding WQ.

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Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.

Abstract

We have previously demonstrated that clioquinol (5-chloro-7-iodo-8-hydroxyquinoline) acts as a zinc ionophore and induces apoptosis of human cancer cells; however, the mechanisms of clioquinol/zinc-induced apoptotic cell death remain to be elucidated further. Using fluorescence-labelled probes, the present study has examined intracellular zinc distribution after clioquinol treatment in human cancer cells in order to identify cellular targets for zinc ionophores. DU 145, a human prostate cancer line, was chosen as a model system for the present study, and results were confirmed in other human cancer cell lines. Although treatment of cancer cells with 50 microM ZnCl2 for 3 days had no effect on cell viability, addition of clioquinol dramatically enhanced the cytotoxicity, confirming our previous observations. The ionophore activity of clioquinol was confirmed using fluorescence microscopy. Intracellular free zinc was found to be concentrated in lysosomes, indicating that lysosomes are the primary target of zinc ionophores. Furthermore, lysosomal integrity was disrupted after addition of clioquinol and zinc to the cells, as shown by redistribution of both Acridine Orange and cathepsin D. Clioquinol plus zinc resulted in a cleavage of Bid (BH3-interacting domain death agonist), a hallmark of lysosome-mediated apoptotic cell death. Thus the present study demonstrates for the first time that clioquinol generates free zinc in lysosomes, leading to their disruption and apoptotic cell death.

PMID:
18764784
[PubMed - indexed for MEDLINE]




Breast Cancer Res. 2005;7(6):R897-908. Epub 2005 Sep 20.
Clioquinol and pyrrolidine dithiocarbamate complex with copper to form proteasome inhibitors and apoptosis inducers in human breast cancer cells.

Daniel KG, Chen D, Orlu S, Cui QC, Miller FR, Dou QP.

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The Prevention Program, Barbara Ann Karmanos Cancer Institute, and Department of Pathology, School of Medicine, Wayne State University, Detroit, Michigan, USA. danielk@karmanos.org

Abstract

INTRODUCTION:

A physiological feature of many tumor tissues and cells is the tendency to accumulate high concentrations of copper. While the precise role of copper in tumors is cryptic, copper, but not other trace metals, is required for angiogenesis. We have recently reported that organic copper-containing compounds, including 8-hydroxyquinoline-copper(II) and 5,7-dichloro-8-hydroxyquinoline-copper(II), comprise a novel class of proteasome inhibitors and tumor cell apoptosis inducers. In the current study, we investigate whether clioquinol (CQ), an analog of 8-hydroxyquinoline and an Alzheimer's disease drug, and pyrrolidine dithiocarbamate (PDTC), a known copper-binding compound and antioxidant, can interact with copper to form cancer-specific proteasome inhibitors and apoptosis inducers in human breast cancer cells. Tetrathiomolybdate (TM), a strong copper chelator currently being tested in clinical trials, is used as a comparison.
METHODS:

Breast cell lines, normal, immortalized MCF-10A, premalignant MCF10AT1K.cl2, and malignant MCF10DCIS.com and MDA-MB-231, were treated with CQ or PDTC with or without prior interaction with copper, followed by measurement of proteasome inhibition and cell death. Inhibition of the proteasome was determined by levels of the proteasomal chymotrypsin-like activity and ubiquitinated proteins in protein extracts of the treated cells. Apoptotic cell death was measured by morphological changes, Hoechst staining, and poly(ADP-ribose) polymerase cleavage.
RESULTS:

When in complex with copper, both CQ and PDTC, but not TM, can inhibit the proteasome chymotrypsin-like activity, block proliferation, and induce apoptotic cell death preferentially in breast cancer cells, less in premalignant breast cells, but are non-toxic to normal/non-transformed breast cells at the concentrations tested. In contrast, CQ, PDTC, TM or copper alone had no effects on any of the cells. Breast premalignant or cancer cells that contain copper at concentrations similar to those found in patients, when treated with just CQ or PDTC alone, but not TM, undergo proteasome inhibition and apoptosis.
CONCLUSION:

The feature of breast cancer cells and tissues to accumulate copper can be used as a targeting method for anticancer therapy through treatment with novel compounds such as CQ and PDTC that become active proteasome inhibitors and breast cancer cell killers in the presence of copper.

PMID:
16280039
[PubMed - indexed for MEDLINE]

PMCID: PMC1410741


Cancer Res. 2007 Feb 15;67(4):1636-44.
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 D, Cui QC, Yang H, Barrea RA, Sarkar FH, Sheng S, Yan B, Reddy GP, Dou QP.

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Barbara Ann Karmanos Cancer Institute and Department of Pathology, School of Medicine, Wayne State University, 4100 John R Road, Detroit, MI 48201, USA.

Abstract

Tumor growth and metastasis depend on angiogenesis that requires the cofactor copper. Consistently, high levels of copper have been found in many types of human cancers, including prostate, breast, colon, and lung. Recent studies suggest that copper could be used as a novel selective target for cancer therapies. Clioquinol is capable of forming stable complexes with copper and currently used in clinics for treatment of Alzheimer's disease. Most recently, it has been reported that clioquinol possesses antitumor effects. However, the underlying molecular mechanism is unclear. We report here that after binding to copper, clioquinol can inhibit the proteasomal chymotrypsin-like activity, repress androgen receptor (AR) protein expression, and induce apoptotic cell death in human prostate cancer LNCaP and C4-2B cells. In addition, clioquinol alone exhibits similar effects in prostate cancer cell lines with elevated copper at concentrations similar to those found in patients. Addition of dihydrotestosterone did not affect clioquinol-mediated proteasome inhibition in both prostate cancer cell lines. However, dihydrotestosterone partially inhibited clioquinol-induced AR suppression and apoptosis only in androgen-dependent LNCaP cells. Animal studies show that clioquinol treatment significantly inhibits the growth of human prostate tumor C4-2B xenografts (by 66%), associated with in vivo proteasome inhibition, AR protein repression, angiogenesis suppression, and apoptosis induction. Our study provides strong evidence that clioquinol is able to target tumor proteasome in vivo in a copper-dependent manner, resulting in formation of an active AR inhibitor and apoptosis inducer that is responsible for its observed antiprostate tumor effect.

PMID:
17308104
[PubMed - indexed for MEDLINE]





Biochem Pharmacol. 2009 May 1;77(9):1480-6. Epub 2009 Feb 13.
PPARalpha signaling mediates the synergistic cytotoxicity of clioquinol and docosahexaenoic acid in human cancer cells.

Tuller ER, Brock AL, Yu H, Lou JR, Benbrook DM, Ding WQ.

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Source

Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.

Abstract

This study investigated the involvement of PPARgamma and PPARalpha signaling in the synergistic anticancer activity of clioquinol (5-chloro-7-iodo-8-hydroxyquinoline) and docosahexaenoic acid (DHA) in human cancer cells. The synergistic cytotoxicity of DHA and clioquinol was demonstrated in nine human cancer cell lines representing different tissues of origin. A2780, a well-established ovarian cancer model system, was chosen for further characterization because of its sensitivity to DHA and clioquinol. Both PPARalpha and PPARgamma were expressed in A2780 cells when analyzed with western blotting and reporter gene technique. Treatment of the cells with clofibrate (a PPARalpha agonist) and clioquinol for three days mimicked the synergy of DHA and clioquinol, whereas this synergy could not be seen with the use of troglitazone (a PPARgamma agonist) and clioquinol, suggesting that PPARalpha signaling is involved in the synergistic action. When used alone, the IC50 of clofibrate was 513 microM in A2780 cells. However, the addition of 5 microM clioquinol to clofibrate-treated cells led to a dramatic reduction of its IC50 value (148 microM). The combination effects index (CI) analysis confirmed the synergy of clioquinol and clofibrate on inhibiting cancer cell viability. Using inhibitors to block PPARalpha signaling diminished the synergistic cytotoxicity of clioquinol and DHA. These results provide pharmacological evidence that the synergistic anticancer action of clioquinol and DHA is mediated by PPARalpha signaling in human cancer cells.

PMID:
19426685


IUBMB Life. 2009 Nov;61(11):1013-8.
Metal ionophores - an emerging class of anticancer drugs.

Ding WQ, Lind SE.
Source

Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. weiqun-ding@ouhsc.edu

Abstract

Compounds that bind metals such as copper and zinc have many biological activities, including the ability to induce apoptosis in cancer cells. Although some of these compounds have been considered to act as chelators of metals, decreasing their bioavailability, others increase intracellular metal concentrations. We review recent work regarding the recognition of the biological effects of metal ionophores with different structures, particularly with regard to their actions upon cancer cells focusing on dithiocarbamates, pyrithione, and the 8-hydroxyquinoline derivative, clioquinol. We provide a biologically based classification of metal-binding compounds that allows an experimental distinction between chelators and ionophores that can be readily used by biologists, which may lead to further study and classification of metal-binding drugs. Metal ionophores may kill cancer cells by a number of mechanisms, including lysosomal disruption and proteasome inhibition, and likely others. Because some of these compounds have been safely administered to animals and humans, they have the potential to become clinically useful anticancer agents.

PMID:
19859983
[PubMed - indexed for MEDLINE]



Toxicol Lett. 2008 Nov 10;182(1-3):1-6. Epub 2008 Sep 4.
The toxicology of Clioquinol.

Mao X, Schimmer AD.

LINK

Source

Ontario Cancer Institute, Princess Margaret Hospital, Toronto, ON, Canada.

Abstract

5-Chloro-7-iodo-quinolin-8-ol (Clioquinol) is a halogenated 8-hydroxyquinoline that was used in 1950-1970s as an oral anti-parasitic agent for the treatment and prevention of intestinal amebiasis. However in the 1970s oral Clioquinol was withdrawn from the market due to reports of neurotoxicity in Japanese patients. Recently, reports have demonstrated that Clioquinol has activities beyond its use as an antimicrobial. For example, Clioquinol inhibits the function of the proteasome and displays preclinical efficacy in the treatment of malignancy. In addition, due to its ability to bind copper and dissolve beta-amyloid plaques in the brain, Clioquinol has been investigated for the treatment of Alzheimer's disease. As such, efforts are underway to repurpose Clioquinol. In light of the reemergence of oral Clioquinol, we review the toxicology of this compound in animals and humans with an emphasis on its neurotoxicity. Such information will aid in the design of clinical trials of oral Clioquinol for new indications such as cancer therapy.

PMID:
18812216
[PubMed - indexed for MEDLINE]



J Pharmacol Exp Ther. 2008 Jan;324(1):360-7. Epub 2007 Oct 16.
Clioquinol promotes cancer cell toxicity through tumor necrosis factor alpha release from macrophages.

Du T, Filiz G, Caragounis A, Crouch PJ, White AR.

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Source

Centre for Neuroscience and Department of Pathology, University of Melbourne, Victoria, Australia 3010. arwhite@unimelb.edu.au.

Abstract

Copper has an important role in cancer growth, angiogenesis, and metastasis. Previous studies have shown that cell-permeable metal ligands, including clioquinol (CQ) and pyrrolidine dithiocarbamate, inhibit cancer cell growth in cell culture and in vivo. The mechanism of action has not been fully determined but may involve metal-mediated inhibition of cancer cell proteasome activity. However, these studies do not fully account for the ability of cell-permeable metal ligands to inhibit cancer cell growth without affecting normal cells. In this study, we examined the effect of CQ on macrophage-mediated inhibition of HeLa cancer cell growth in vitro. When CQ was added to RAW 264.7 macrophage-HeLa cell cocultures, a substantial increase in HeLa cell toxicity was observed compared with CQ treatment of HeLa cells cultured alone. Transfer of conditioned medium from CQ-treated macrophages to HeLa cells also induced HeLa cell toxicity, demonstrating the role of secreted factors in the macrophage-mediated effect. Further investigation revealed that CQ induced copper-dependent activation of macrophages and release of tumor necrosis factor (TNF) alpha. In studies with recombinant TNFalpha, we showed that the level of TNFalpha released by CQ-treated macrophages was sufficient to induce HeLa cell toxicity. Moreover, the toxic effect of conditioned medium from CQ-treated macrophages could be prevented by addition of neutralizing antibodies to TNFalpha. These studies demonstrate that CQ can induce cancer cell toxicity through metal-dependent release of TNFalpha from macrophages. Our results may help to explain the targeted inhibition of tumor growth in vivo by CQ.

PMID:
17940196
[PubMed - indexed for MEDLINE]
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Old 06-23-2011, 09:05 PM   #2
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Re: Clioquinol (antibiotic, chelator)

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Old 06-23-2011, 09:06 PM   #3
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Re: Clioquinol (antibiotic, chelator)

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