Feasibility of Repurposing Clioquinol for Cancer Therapy

Author(s): Raheel Khan, Harras Khan, Yassen Abdullah, Q. Ping Dou*

Journal Name: Recent Patents on Anti-Cancer Drug Discovery

Volume 15 , Issue 1 , 2020

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Abstract:

Background: Cancer is a prevalent disease in the world and is becoming more widespread as time goes on. Advanced and more effective chemotherapeutics need to be developed for the treatment of cancer to keep up with this prevalence. Repurposing drugs is an alternative to discover new chemotherapeutics. Clioquinol is currently being studied for reposition as an anti-cancer drug.

Objective: This study aimed to summarize the anti-cancer effects of clioquinol and its derivatives through a detailed literature and patent review and to review their potential re-uses in cancer treatment.

Methods: Research articles were collected through a PubMed database search using the keywords “Clioquinol” and “Cancer.” The keywords “Clioquinol Derivatives” and “Clioquinol Analogues” were also used on a PubMed database search to gather research articles on clioquinol derivatives. Patents were gathered through a Google Patents database search using the keywords “Clioquinol” and “Cancer.”

Results: Clioquinol acts as a copper and zinc ionophore, a proteasome inhibitor, an anti-angiogenesis agent, and is an inhibitor of key signal transduction pathways responsible for its growth-inhibitory activity and cytotoxicity in cancer cells preclinically. A clinical trial conducted by Schimmer et al., resulted in poor outcomes that prompted studies on alternative clioquinol-based applications, such as new combinations, new delivery methods, or new clioquinol-derived analogues. In addition, numerous patents claim alternative uses of clioquinol for cancer therapy.

Conclusion: Clioquinol exhibits anti-cancer activities in many cancer types, preclinically. Low therapeutic efficacy in a clinical trial has prompted new studies that aim to discover more effective clioquinol- based cancer therapies.

Keywords: Cancer, clioquinol, copper ionophore, cytotoxicity, proteasome, zinc ionophore.

[1]
Sleire L, Førde HE, Netland IA, Leiss L, Skeie BS, Enger PO. Drug repurposing in cancer. Pharmacol Res 2017; 124: 74-91.
[http://dx.doi.org/10.1016/j.phrs.2017.07.013] [PMID: 28712971]
[2]
Cha Y, Erez T, Reynolds IJ, et al. Drug repurposing from the perspective of pharmaceutical companies. Br J Pharmacol 2018; 175(2): 168-80.
[http://dx.doi.org/10.1111/bph.13798] [PMID: 28369768]
[3]
Pushpakom S, Iorio F, Eyers PA, et al. Drug repurposing: progress, challenges and recommendations. Nat Rev Drug Discov 2019; 18(1): 41-58.
[http://dx.doi.org/10.1038/nrd.2018.168] [PMID: 30310233]
[4]
Arbiser JL, Kraeft S-K, Leeuwen R van, et al. Clioquinol-zinc chelate: a candidate causative agent of subacute myelo-optic neuropathy. Mol Med 1998; 4(10): 665-70.
[http://dx.doi.org/10.1007/BF03401927] [PMID: 9848083]
[5]
Tateishi J. Subacute myelo-optico-neuropathy: clioquinol intoxication in humans and animals. Neuropathology 2000; 20: S20-4.
[http://dx.doi.org/10.1046/j.1440-1789.2000.00296.x] [PMID: 11037182]
[6]
Konagaya M. [SMON: toxicity of clioquinol and the status quo]. Brain Nerve 2015; 67(1): 49-62.
[PMID: 25585435]
[7]
Perez DR, Sklar LA, Chigaev A. Clioquinol: To harm or heal. Pharmacol Ther 2019; 199: 155-63.
[http://dx.doi.org/10.1016/j.pharmthera.2019.03.009] [PMID: 30898518]
[8]
Benvenisti-Zarom L, Chen J, Regan RF. The oxidative neurotoxicity of clioquinol. Neuropharmacology 2005; 49(5): 687-94.
[http://dx.doi.org/10.1016/j.neuropharm.2005.04.023] [PMID: 15992834]
[9]
Mao X, Schimmer AD. The toxicology of Clioquinol. Toxicol Lett 2008; 182(1-3): 1-6.
[http://dx.doi.org/10.1016/j.toxlet.2008.08.015] [PMID: 18812216]
[10]
Bareggi SR, Cornelli U. Clioquinol: review of its mechanisms of action and clinical uses in neurodegenerative disorders. CNS Neurosci Ther 2012; 18(1): 41-6.
[http://dx.doi.org/10.1111/j.1755-5949.2010.00231.x] [PMID: 21199452]
[11]
McInerney MP, Volitakis I, Bush AI, Banks WA, Short JL, Nicolazzo JA. Ionophore and biometal modulation of p-glycoprotein expression and function in human brain microvascular endothelial cells. Pharm Res 2018; 35(4): 83.
[http://dx.doi.org/10.1007/s11095-018-2377-6] [PMID: 29508078]
[12]
Melov S. '...and C is for Clioquinol’ - the AbetaCs of Alzheimer’s disease. Trends Neurosci 2002; 25(3): 121-3.
[http://dx.doi.org/10.1016/S0166-2236(00)02086-5] [PMID: 11852134]
[13]
Mao F, Yan J, Li J, et al. New multi-target-directed small molecules against Alzheimer’s disease: a combination of resveratrol and clioquinol. Org Biomol Chem 2014; 12(31): 5936-44.
[http://dx.doi.org/10.1039/C4OB00998C] [PMID: 24986600]
[14]
Regland B, Lehmann W, Abedini I, et al. Treatment of Alzheimer’s disease with clioquinol. Dement Geriatr Cogn Disord 2001; 12(6): 408-14.
[http://dx.doi.org/10.1159/000051288] [PMID: 11598313]
[15]
Opazo C, Luza S, Villemagne VL, et al. Radioiodinated clioquinol as a biomarker for beta-amyloid: Zn complexes in Alzheimer’s disease. Aging Cell 2006; 5(1): 69-79.
[http://dx.doi.org/10.1111/j.1474-9726.2006.00196.x] [PMID: 16441845]
[16]
Barcia E, Salama A, Fernández-Carballido A, Negro S. Protective effects of clioquinol on human neuronal-like cells: a new formulation of clioquinol-loaded PLGA microspheres for Alzheimer’s disease. J Drug Target 2011; 19(8): 637-46.
[http://dx.doi.org/10.3109/1061186X.2010.523789] [PMID: 20945972]
[17]
Wang T, Zheng W, Xu H, Zhou J-M, Wang Z-Y. Clioquinol inhibits zinc-triggered caspase activation in the hippocampal CA1 region of a global ischemic gerbil model. PLoS One 2010; 5(7) e11888
[http://dx.doi.org/10.1371/journal.pone.0011888] [PMID: 20686690]
[18]
Duncan C, White AR. Copper complexes as therapeutic agents. Metallomics 2012; 4(2): 127-38.
[http://dx.doi.org/10.1039/C2MT00174H] [PMID: 22187112]
[19]
Frezza M, Hindo S, Chen D, et al. Novel metals and metal complexes as platforms for cancer therapy. Curr Pharm Des 2010; 16(16): 1813-25.
[http://dx.doi.org/10.2174/138161210791209009] [PMID: 20337575]
[20]
Zhai S, Yang L, Cui QC, Sun Y, Dou QP, Yan B. Tumor cellular proteasome inhibition and growth suppression by 8-hydroxyquinoline and clioquinol requires their capabilities to bind copper and transport copper into cells. J Biol Inorg Chem 2010; 15(2): 259-69.
[http://dx.doi.org/10.1007/s00775-009-0594-5] [PMID: 19809836]
[21]
Franklin RB, Zou J, Costello LC. The cytotoxic role of RREB1, ZIP3 zinc transporter, and zinc in human pancreatic adenocarcinoma. Cancer Biol Ther 2014; 15(10): 1431-7.
[http://dx.doi.org/10.4161/cbt.29927] [PMID: 25050557]
[22]
Costello LC, Franklin RB. Cytotoxic/tumor suppressor role of zinc for the treatment of cancer: an enigma and an opportunity. Expert Rev Anticancer Ther 2012; 12(1): 121-8.
[http://dx.doi.org/10.1586/era.11.190] [PMID: 22149438]
[23]
Daniel KG, Chen D, Orlu S, Cui QC, Miller FR, Dou QP. Clioquinol and pyrrolidine dithiocarbamate complex with copper to form proteasome inhibitors and apoptosis inducers in human breast cancer cells. Breast Cancer Res 2005; 7(6): R897-908.
[http://dx.doi.org/10.1186/bcr1322] [PMID: 16280039]
[24]
Ding WQ, Liu B, Vaught JL, Yamauchi H, Lind SE. Anticancer activity of the antibiotic clioquinol. Cancer Res 2005; 65(8): 3389-95.
[http://dx.doi.org/10.1158/0008-5472.CAN-04-3577] [PMID: 15833873]
[25]
Zhang H, Chen D, Ringler J, et al. Disulfiram treatment facilitates phosphoinositide 3-kinase inhibition in human breast cancer cells in vitro and in vivo. Cancer Res 2010; 70(10): 3996-4004.
[http://dx.doi.org/10.1158/0008-5472.CAN-09-3752] [PMID: 20424113]
[26]
Zheng J, Benbrook DM, Yu H, Ding WQ. Clioquinol suppresses cyclin D1 gene expression through transcriptional and post-transcriptional mechanisms. Anticancer Res 2011; 31(9): 2739-47.
[PMID: 21868515]
[27]
Zheng J, Zhang XX, Yu H, Taggart JE, Ding WQ. Zinc at cytotoxic concentrations affects posttranscriptional events of gene expression in cancer cells. Cell Physiol Biochem 2012; 29(1-2): 181-8.
[http://dx.doi.org/10.1159/000337599] [PMID: 22415087]
[28]
Xue J, Wang S, Wu J, Hannafon BN, Ding WQ. Zinc at sub-cytotoxic concentrations induces heme oxygenase-1 expression in human cancer cells. Cell Physiol Biochem 2013; 32(1): 100-10.
[http://dx.doi.org/10.1159/000350128] [PMID: 23868099]
[29]
Lu S, Ke Y, Wu C, et al. Radiosensitization of clioquinol and zinc in human cancer cell lines. BMC Cancer 2018; 18(1): 448.
[http://dx.doi.org/10.1186/s12885-018-4264-2] [PMID: 29678153]
[30]
Kumar S, Ahmad MK, Waseem M, Pandey AK. Drug targets for cancer treatment: An overview. Med Chem (Los Angeles) 2015; 5(3): 115-23.
[http://dx.doi.org/10.4172/2161-0444.1000252]
[31]
Cao B, Li J, Zhu J, et al. The antiparasitic clioquinol induces apoptosis in leukemia and myeloma cells by inhibiting histone deacetylase activity. J Biol Chem 2013; 288(47): 34181-9.
[http://dx.doi.org/10.1074/jbc.M113.472563] [PMID: 24114842]
[32]
Cao B, Li J, Zhou X, et al. Clioquinol induces pro-death autophagy in leukemia and myeloma cells by disrupting the mTOR signaling pathway. Sci Rep 2014; 4(5749): 5749.
[PMID: 25034786]
[33]
Mao H, Wang M, Cao B, Zhou H, Zhang Z, Mao X. Interferon-stimulated gene 15 induces cancer cell death by suppressing the NF-κB signaling pathway. Oncotarget 2016; 7(43): 70143-51.
[http://dx.doi.org/10.18632/oncotarget.12160] [PMID: 27659523]
[34]
Perez D, Simons PC, Smagley Y, Sklar LA, Chigaev A. A high throughput flow cytometry assay for identification of inhibitors of 3′:5′-cyclic adenosine monophosphate efflux. Methods Mol Biol 2016; 1439: 227-44.
[http://dx.doi.org/10.1007/978-1-4939-3673-1_15] [PMID: 27316999]
[35]
Mao X, Li X, Sprangers R, et al. Clioquinol inhibits the proteasome and displays preclinical activity in leukemia and myeloma. Leukemia 2009; 23(3): 585-90.
[http://dx.doi.org/10.1038/leu.2008.232] [PMID: 18754030]
[36]
Perez DR, Smagley Y, Garcia M, et al. Cyclic AMP efflux inhibitors as potential therapeutic agents for leukemia. Oncotarget 2016; 7(23): 33960-82.
[http://dx.doi.org/10.18632/oncotarget.8986] [PMID: 27129155]
[37]
Carpentieri U, Myers J, Thorpe L, Daeschner CW III, Haggard ME. Copper, zinc, and iron in normal and leukemic lymphocytes from children. Cancer Res 1986; 46(2): 981-4.
[PMID: 3455680]
[38]
Chen D, Cui QC, Yang H, et al. 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. Cancer Res 2007; 67(4): 1636-44.
[http://dx.doi.org/10.1158/0008-5472.CAN-06-3546] [PMID: 17308104]
[39]
Barrea RA, Chen D, Irving TC, Dou QP. Synchrotron X-ray imaging reveals a correlation of tumor copper speciation with Clioquinol’s anticancer activity. J Cell Biochem 2009; 108(1): 96-105.
[http://dx.doi.org/10.1002/jcb.22231] [PMID: 19530227]
[40]
Cater MA, Haupt Y. Clioquinol induces cytoplasmic clearance of the X-linked inhibitor of apoptosis protein (XIAP): therapeutic indication for prostate cancer. Biochem J 2011; 436(2): 481-91.
[http://dx.doi.org/10.1042/BJ20110123] [PMID: 21426304]
[41]
Yu H, Zhou Y, Lind SE, Ding W-Q. Clioquinol targets zinc to lysosomes in human cancer cells. Biochem J 2009; 417(1): 133-9.
[http://dx.doi.org/10.1042/BJ20081421] [PMID: 18764784]
[42]
Yu H, Lou JR, Ding WQ. Clioquinol independently targets NF-kappaB and lysosome pathways in human cancer cells. Anticancer Res 2010; 30(6): 2087-92.
[PMID: 20651355]
[43]
Costello LC, Franklin RB. A proposed efficacious treatment with clioquinol (zinc ionophore) and cabergoline (prolaction dopamine agonist) for the treatment of terminal androgen-independent prostate cancer. Why and how? J Clin Oncol 2019; 2(1): 1-15.
[44]
Franklin RB, Zou J, Zheng Y, Naslund MJ, Costello LC. Zinc ionophore clioquinol inhibition of hZIP1 deficient prostate tumor growth in the mouse. Int J Cancer Clin Res 2016; 3(1): 1-11.
[http://dx.doi.org/10.23937/2378-3419/3/1/1037] [PMID: 26878064]
[45]
Huang Z, Wang L, Chen L, Zhang Y, Shi P. Induction of cell cycle arrest via the p21, p27-cyclin E,A/Cdk2 pathway in SMMC-7721 hepatoma cells by clioquinol. Acta Pharm 2015; 65(4): 463-71.
[http://dx.doi.org/10.1515/acph-2015-0034] [PMID: 26677902]
[46]
Chan-On W, Huyen NTB, Songtawee N, Suwanjang W, Prachayasittikul S, Prachayasittikul V. Quinoline-based clioquinol and nitroxoline exhibit anticancer activity inducing FoxM1 inhibition in cholangiocarcinoma cells. Drug Des Devel Ther 2015; 9: 2033-47.
[PMID: 25897210]
[47]
Du T, Filiz G, Caragounis A, Crouch PJ, White AR. Clioquinol promotes cancer cell toxicity through tumor necrosis factor alpha release from macrophages. J Pharmacol Exp Ther 2008; 324(1): 360-7.
[http://dx.doi.org/10.1124/jpet.107.130377] [PMID: 17940196]
[48]
Ding WQ, Yu HJ, Lind SE. Zinc-binding compounds induce cancer cell death via distinct modes of action. Cancer Lett 2008; 271(2): 251-9.
[http://dx.doi.org/10.1016/j.canlet.2008.06.011] [PMID: 18639975]
[49]
Katsuyama M, Iwata K, Ibi M, Matsuno K, Matsumoto M, Yabe-Nishimura C. Clioquinol induces DNA double-strand breaks, activation of ATM, and subsequent activation of p53 signaling. Toxicology 2012; 299(1): 55-9.
[http://dx.doi.org/10.1016/j.tox.2012.05.013] [PMID: 22627294]
[50]
Kawamura K, Kuroda Y, Sogo M, Fujimoto M, Inui T, Mitsui T. Superoxide dismutase as a target of clioquinol-induced neurotoxicity. Biochem Biophys Res Commun 2014; 452(1): 181-5.
[http://dx.doi.org/10.1016/j.bbrc.2014.04.067] [PMID: 24755073]
[51]
Schimmer AD, Jitkova Y, Gronda M, et al. A phase I study of the metal ionophore clioquinol in patients with advanced hematologic malignancies. Clin Lymphoma Myeloma Leuk 2012; 12(5): 330-6.
[http://dx.doi.org/10.1016/j.clml.2012.05.005] [PMID: 22683301]
[52]
Wehbe M, Malhotra AK, Anantha M, et al. Development of a copper-clioquinol formulation suitable for intravenous use. Drug Deliv Transl Res 2018; 8(1): 239-51.
[http://dx.doi.org/10.1007/s13346-017-0455-7] [PMID: 29247315]
[53]
Tsai W, Tsai H, Wong Y, Hong J, Chang S, Lee M. Preparation and characterization of gellan gum/glucosamine/clioquinol film as oral cancer treatment patch. Mater Sci Eng C 2018; 82: 317-22.
[http://dx.doi.org/10.1016/j.msec.2017.05.040] [PMID: 29025664]
[54]
Jiang H, Xing J, Wang C, et al. Discovery of novel BET inhibitors by drug repurposing of nitroxoline and its analogues. Org Biomol Chem 2017; 15(44): 9352-61.
[http://dx.doi.org/10.1039/C7OB02369C] [PMID: 29087414]
[55]
Mao H, Du Y, Zhang Z, et al. Nitroxoline shows antimyeloma activity by targeting the TRIM25/p53 axle. Anticancer Drugs 2017; 28(4): 376-83.
[http://dx.doi.org/10.1097/CAD.0000000000000466] [PMID: 28301380]
[56]
Li X, Wood TE, Sprangers R, et al. Effect of noncompetitive proteasome inhibition on bortezomib resistance. J Natl Cancer Inst 2010; 102(14): 1069-82.
[http://dx.doi.org/10.1093/jnci/djq198] [PMID: 20505154]
[57]
Yu JG, Ji CH, Shi MH. Nitroxoline induces cell apoptosis by inducing MDM2 degradation in small-cell lung cancer. Kaohsiung J Med Sci 2019; 35(4): 202-8.
[http://dx.doi.org/10.1002/kjm2.12051] [PMID: 30896891]
[58]
Veschi S, De Lellis L, Florio R, et al. Effects of repurposed drug candidates nitroxoline and nelfinavir as single agents or in combination with erlotinib in pancreatic cancer cells. J Exp Clin Cancer Res 2018; 37(1): 236.
[http://dx.doi.org/10.1186/s13046-018-0904-2] [PMID: 30241558]
[59]
Kim YH, Woo KJ, Lim JH, et al. 8-Hydroxyquinoline inhibits iNOS expression and nitric oxide production by down-regulating LPS-induced activity of NF-kappaB and C/EBPbeta in Raw 264.7 cells. Biochem Biophys Res Commun 2005; 329(2): 591-7.
[http://dx.doi.org/10.1016/j.bbrc.2005.01.159] [PMID: 15737626]
[60]
Pun IHY, Chan D, Chan SH, et al. Anti-cancer effects of a novel quinoline derivative 83b1 on human esophageal squamous cell carcinoma through down-regulation of COX-2 mRNA and PGE2. Cancer Res Treat 2017; 49(1): 219-29.
[http://dx.doi.org/10.4143/crt.2016.190] [PMID: 27456944]
[61]
Joshi PV, Sayed AA, RaviKumar A, Puranik VG, Zinjarde SS. 4-Phenyl quinoline derivatives as potential serotonin receptor ligands with antiproliferative activity. Eur J Med Chem 2017; 136: 246-58.
[http://dx.doi.org/10.1016/j.ejmech.2017.05.002] [PMID: 28499170]
[62]
Mitrović A, Sosič I, Kos Š, et al. Addition of 2-(ethylamino)acetonitrile group to nitroxoline results in significantly improved anti-tumor activity in vitro and in vivo. Oncotarget 2017; 8(35): 59136-47.
[http://dx.doi.org/10.18632/oncotarget.19296] [PMID: 28938624]
[63]
Shaw AY, Chang CY, Hsu MY, et al. Synthesis and structure-activity relationship study of 8-hydroxyquinoline-derived Mannich bases as anticancer agents. Eur J Med Chem [Internet] 2010; 45(7): 2860-7.
[http://dx.doi.org/10.1016/j.ejmech.2010.03.008] [PMID: 20359788]
[64]
Zhang YL, Qin QP, Cao QQ, et al. Synthesis, crystal structure, cytotoxicity and action mechanism of a Rh(iii) complex with 8-hydroxy-2-methylquinoline as a ligand. MedChemComm 2016; 8(1): 184-90.
[http://dx.doi.org/10.1039/C6MD00462H] [PMID: 30108704]
[65]
Xie F, Peng F. Anti-Prostate Cancer Activity of 8-Hydroxyquinoline-2-carboxaldehyde-thiosemicarbazide copper complexes by fluorescent microscopic imaging. J Fluoresc 2017; 27(6): 1937-41.
[http://dx.doi.org/10.1007/s10895-017-2133-z] [PMID: 28653241]
[66]
Chan SH, Chui CH, Chan SW, et al. Synthesis of 8-hydroxyquinoline derivatives as novel antitumor agents. ACS Med Chem Lett 2012; 4(2): 170-4.
[http://dx.doi.org/10.1021/ml300238z] [PMID: 24900641]
[67]
Ariyasu S, Sawa A, Morita A, et al. Design and synthesis of 8-hydroxyquinoline-based radioprotective agents. Bioorg Med Chem 2014; 22(15): 3891-905.
[http://dx.doi.org/10.1016/j.bmc.2014.06.017] [PMID: 25002230]
[68]
Barilli A, Atzeri C, Bassanetti I, et al. Oxidative stress induced by copper and iron complexes with 8-hydroxyquinoline derivatives causes paraptotic death of HeLa cancer cells. Mol Pharm 2014; 11(4): 1151-63.
[http://dx.doi.org/10.1021/mp400592n] [PMID: 24592930]
[69]
Jiang H, Taggart JE, Zhang X, Benbrook DM, Lind SE, Ding W-Q. Nitroxoline (8-hydroxy-5-nitroquinoline) is more a potent anti-cancer agent than clioquinol (5-chloro-7-iodo-8-quinoline). Cancer Lett 2011; 312(1): 11-7.
[http://dx.doi.org/10.1016/j.canlet.2011.06.032] [PMID: 21899946]
[70]
Shim JS, Matsui Y, Bhat S, et al. Effect of nitroxoline on angiogenesis and growth of human bladder cancer. J Natl Cancer Inst 2010; 102(24): 1855-73.
[http://dx.doi.org/10.1093/jnci/djq457] [PMID: 21088277]
[71]
Chen HL, Chang CY, Lee HT, et al. Synthesis and pharmacological exploitation of clioquinol-derived copper-binding apoptosis inducers triggering reactive oxygen species generation and MAPK pathway activation. Bioorg Med Chem 2009; 17(20): 7239-47.
[http://dx.doi.org/10.1016/j.bmc.2009.08.054] [PMID: 19748786]
[72]
Oliveri V, Viale M, Caron G, Aiello C, Gangemi R, Vecchio G. Glycosylated copper(II) ionophores as prodrugs for β-glucosidase activation in targeted cancer therapy. Dalton Trans 2013; 42(6): 2023-34.
[http://dx.doi.org/10.1039/C2DT32429F] [PMID: 23174818]
[73]
Oliveri V, Giuffrida ML, Vecchio G, Aiello C, Viale M. Gluconjugates of 8-hydroxyquinolines as potential anti-cancer prodrugs. Dalton Trans 2012; 41(15): 4530-5.
[http://dx.doi.org/10.1039/c2dt12371a] [PMID: 22354329]
[74]
Tuller ER, Brock AL, Yu H, Lou JR, Benbrook DM, Ding WQ. PPARalpha signaling mediates the synergistic cytotoxicity of clioquinol and docosahexaenoic acid in human cancer cells. Biochem Pharmacol 2009; 77(9): 1480-6.
[http://dx.doi.org/10.1016/j.bcp.2009.02.002] [PMID: 19426685]
[75]
Ding W-Q, Liu B, Vaught JL, Palmiter RD, Lind SE. Clioquinol and docosahexaenoic acid act synergistically to kill tumor cells. Mol Cancer Ther 2006; 5(7): 1864-72.
[http://dx.doi.org/10.1158/1535-7163.MCT-06-0067] [PMID: 16891473]
[76]
Denoyer D, Pearson HB, Clatworthy SAS, et al. Copper as a target for prostate cancer therapeutics: copper-ionophore pharmacology and altering systemic copper distribution. Oncotarget 2016; 7(24): 37064-80.
[http://dx.doi.org/10.18632/oncotarget.9245] [PMID: 27175597]
[77]
He M, Luo M, Liu Q, et al. Combination treatment with fasudil and clioquinol produces synergistic anti-tumor effects in U87 glioblastoma cells by activating apoptosis and autophagy. J Neurooncol 2016; 127(2): 261-70.
[http://dx.doi.org/10.1007/s11060-015-2044-2] [PMID: 26725099]
[78]
Bhat S, Shim JS, Zhang F, Chong CR, Liu JO. Substituted oxines inhibit endothelial cell proliferation and angiogenesis. Org Biomol Chem 2012; 10(15): 2979-92.
[http://dx.doi.org/10.1039/c2ob06978d] [PMID: 22391578]
[79]
Gobec M, Kljun J, Sosič I, et al. Structural characterization and biological evaluation of a clioquinol-ruthenium complex with copper-independent antileukaemic activity. Dalton Trans 2014; 43(24): 9045-51.
[http://dx.doi.org/10.1039/C4DT00463A] [PMID: 24781711]
[80]
Mitrović A, Kljun J, Sosič I, Gobec S, Turel I, Kos J. Clioquinol-ruthenium complex impairs tumour cell invasion by inhibiting cathepsin B activity. Dalton Trans 2016; 45(42): 16913-21.
[http://dx.doi.org/10.1039/C6DT02369J] [PMID: 27711842]
[81]
León IE, Díez P, Baran EJ, Etcheverry SB, Fuentes M. Decoding the anticancer activity of VO-clioquinol compound: the mechanism of action and cell death pathways in human osteosarcoma cells. Metallomics 2017; 9(7): 891-901.
[http://dx.doi.org/10.1039/C7MT00068E] [PMID: 28581009]
[82]
Russl-Jones GJ, Luke MR, Himes SR. Transdermal delivery of pharmaceutical agents. US20070243132. (2007).
[83]
LeMahieu E, Jones C, Stern T, et al. Methods and systems of delivering medication via inhalation. US20080066741. (2008).
[84]
Maksoud YAA, Maher MA. Pharmaceutical compositions for intranasal administration for the treatment of neurodegenerative disorders. US8987199. (2015).
[85]
Castaigne J, Demeule M, Che C, Regina A. Compositions and methods for the transport of therapeutic agents. WO2011041897. (2011).
[86]
Bezwada RS. Control release of biologically active compounds from multi-armed oligomers. US8026285. (2011).
[87]
Tsien R, Aguilera T, Olson E, Jiang T, Nguyen Q. Peptides whose uptake in cells is controllable. US9682151. (2017).
[88]
Emanuel N. Sustained-release drug carrier composition. US10105443. (2018).
[89]
Schutt EG, McGuire RW, Walter PA, Los KDA. Method for formulating large diameter synthetic membrane vesicles. US980842. (2017).
[90]
Lind SE, Ding W. Ionophores as a cancer chemotherapeutic agents. US20060040980. (2006).
[91]
Laughlin M, Anderson MB, Willardsen A, Pleiman C. Methods of treating cancer. US20100093773. (2010).
[92]
Tsai C. Hydroxylated tolans and related compounds in the treatment of a cancer. US8716355. (2014).
[93]
Xilinas M. Method for treating cancer, coronary, inflammatory, and macular disease, combining the modulation of zinc and/or copper dependent proteins. US20080207673. (2008).
[94]
Mumper RJ, Gupte A, Wadhwa S. Polymer-metal chelator conjugates and uses thereof. US20090092664. (2009).
[95]
Gomis R, Arnal A, Pavlovic M, Tarragona M. Method of designing a therapy for breast cancer metastasis. EP3091085. (2011).
[96]
Gomis R, Planet E, Pavlovic M, Arnal A, Tarragona M. Method for the prognosis and treatment of metastasizing cancer of the bone originating from breast cancer. EP3055429. (2014).
[97]
Schimmer AD, Mao X, Steward K. Clioquinol for the treatment of hematological malignancies. US20110123617. (2011).
[98]
Schimmer AD, Li X, Batey R, Wood T, Mao X. 8- Hydroxyquinolin derivatives for the treatment of hematoligcal malignancies. US20110144155. (2011).
[99]
Gajewski TF, Sivan A, Corrales L. Treatment of cancer by manipulation of commensal microflora. US98553202. (2018).
[100]
Chigaev A, Sklar LA, Perez D. Method for cancer cell reprogramming. US9314460. (2016).


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Article Details

VOLUME: 15
ISSUE: 1
Year: 2020
Page: [14 - 31]
Pages: 18
DOI: 10.2174/1574892815666200227090259
Price: $65

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