Exploring the versatility of ciclopirox – from anti-fungal to anticancer agent and beyond
DOI:
https://doi.org/10.15584/ejcem.2023.4.26Keywords:
AIDS, anti-fungal, cancer, cardiovascular diseases, ciclopiroxAbstract
Introduction and aim. Ciclopirox has been treating fungal infections for decades. Recent studies suggest ciclopirox may be repurposed to treat cancer, viral infections, and neurological disorders. Ciclopirox exerts anticancer by inhibiting multiple pathways of cancer cell growth and survival and anti-viral actions by reducing viral replication and altering the host immunological response to viral infection. Recent research suggests that ciclopirox may protect against neurodegenerative illnesses including Alzheimer’s and Parkinson’s. This narrative review shows ciclopirox’s potential to treat cancer, viral infections, and neurological diseases.
Material and methods. Current relevant research publications focused on ciclopirox and its repurposing medicinal potential, therefore a well-designed technique was used to find them. „Ciclopirox”, „Anti-fungal”, „Anti-cancer”, „Repurposing”, and „Therapeutic potential” were used to search PubMed, Web of Science, EMBASE, and Google Scholar.
Analysis of literature. Ciclopirox may reduce oxidative stress and inflammation, which may cause several illnesses. Overall, the repurposing of ciclopirox for the treatment of cancer, viral infections, and neurodegenerative disorders represents a promising avenue of research that warrants further investigation.
Conclusion. It was concluded that CPX and olamine derivatives as outstanding antifungal medications, as well as provide information on ongoing research to use them for other illnesses.
Downloads
References
Jue SG, Dawson GW, Brogden RN. Ciclopirox Olamine 1% Cream A Preliminary Review of its Antimicrobial Activity and Therapeutic Use. Drugs. 1985;29(4):330-341. doi: 10.2165/00003495-198529040-00002
Sigle HC, Thewes S, Niewerth M, Korting HC, Schäfer-Korting M, Hube B. Oxygen accessibility and iron levels are critical factors for the antifungal action of ciclopirox against Candida albicans. J Antimicrob Chemother. 2005;55(5):663-673. doi: 10.1093/jac/dki089
Abrams BB. Ciclopirox Olaminer A Hydroxypyridone Antifungal Agent. Clin Dermatol. 1991;9(4):471-417. doi: 10.1016/0738-081x(91)90075-v
Hoque M, Hanauske-Abel HM, Palumbo P, et al. Inhibition of HIV-1 gene expression by Ciclopirox and Deferiprone, drugs that prevent hypusination of eukaryotic initiation factor 5A. Retrovirology. 2009;6:90. doi: 10.1186/1742-4690-6-90
Sonthalia S, Agrawal M, Sehgal VN. Topical Ciclopirox Olamine 1%: Revisiting a Unique Antifungal. Indian Dermatol Online J. 2019;10(4):481-485. doi: 10.4103/idoj.IDOJ_29_19
Piraccini BM, Iorizzo M, Lencastre A, Nenoff P, Rigopoulos D. Ciclopirox Hydroxypropyl Chitosan (HPCH) Nail Lacquer: A Review of Its Use in Onychomycosis. Dermatol Ther (Heidelb). 2020;10(5):917-929. doi: 10.1007/s13555-020-00420-9
Iorizzo M, Hartmane I, Derveniece A, Mikazans I. Ciclopirox 8% HPCH Nail Lacquer in the Treatment of Mild-to-Moderate Onychomycosis: A Randomized, Double-Blind Amorolfine Controlled Study Using a Blinded Evaluator. Skin Appendage Disord. 2016;1(3):134-140. doi: 10.1159/000441569
Saraf V, Mahajan S, Deshmukh G, Dhoot D, Barkate H. Effectiveness and safety of ciclopirox olamine in patients with dermatophytosis: a retrospective cohort analysis. International Journal of Research in Dermatology. 2020;7:38. doi: 10.18203/issn.2455-4529.IntJResDermatol20205592
Kokjohn K, Bradley M, Griffiths B, Ghannoum M. Evaluation of in vitro activity of ciclopirox olamine, butenafine HCl and econazole nitrate against dermatophytes, yeasts and bacteria. Int J Dermatol. 2003;42(1):11-17. doi: 10.1046/j.1365-4362.42.s1.4.x
Niewerth M, Kunze D, Seibold M, Schaller M, Korting HC, Hube B. Ciclopirox Olamine Treatment Affects the Expression Pattern of Candida albicans Genes Encoding Virulence Factors, Iron Metabolism Proteins, and Drug Resistance Factors. Antimicrob Agents Chemother. 2003;47(6):1805-1817. doi: 10.1128/AAC.47.6.1805-1817.2003
Chen L, Chen D, Li J, et al. Ciclopirox drives growth arrest and autophagic cell death through STAT3 in gastric cancer cells. Cell Death Dis. 2022;13(11):1-13. doi: 10.1038/s41419-022-05456-7
Belenky P, Camacho D, Collins JJ. Fungicidal Drugs Induce a Common Oxidative Damage Cellular Death Pathway. Cell Rep. 2013;3(2):350-358. doi: 10.1016/j.celrep.2012.12.021
ciclopirox (CHEBI:453011). https://www.ebi.ac.uk/chebi/searchId.do?chebiId=453011. Accessed November 18, 2022.
Hu L, Feng H, Zhang H, et al. Development of Novel N-hydroxypyridone Derivatives as Potential Anti-Ischemic Stroke Agents. J Med Chem. 2020;63(3):1051-1067. doi: 10.1021/acs.jmedchem.9b01338
Lin J, Zangi M, Kumar TVNH, et al. Synthetic Derivatives of Ciclopirox are Effective Inhibitors of Cryptococcus neoformans. ACS Omega. 2021;6(12):8477-8487. doi: 10.1021/acsomega.1c00273
Liu Z, Yao Y, Kogiso M, et al. Inhibition of Cancer-Associated Mutant Isocitrate Dehydrogenases: Synthesis, Structure–Activity Relationship, and Selective Antitumor Activity. J Med Chem. 2014;57(20):8307-8318. doi: 10.1021/jm500660f
Bohn M, Kraemer KTh. Dermatopharmacology of ciclopirox nail lacquer topical solution 8% in the treatment of onychomycosis. J Am Acad Dermatol. 2000;43(4):57-69. doi: 10.1067/mjd.2000.109072
Sato E, Kohno M, Nakashima T, Niwano Y. Ciclopirox olamine directly scavenges hydroxyl radical: A hydroxyl radical scavenger, ciclopirox olamine. Int J Dermatol. 2007;47(1):15-18. doi: 10.1111/j.1365-4632.2007.03359.x
Nakashima T, Sato E, Niwano Y, Kohno M, Muraoka W, Oda T. Inhibitory or scavenging action of ketoconazole and ciclopiroxolamine against reactive oxygen species released by primed inflammatory cells. Br J Dermatol. 2007;156(4):720-727. doi: 10.1111/j.1365-2133.2006.07655.x
Radadiya PS, Thornton MM, Puri RV, et al. Ciclopirox olamine induces ferritinophagy and reduces cyst burden in polycystic kidney disease. JCI Insight. 2021;6(8):e141299. doi: 10.1172/jci.insight.141299
Kellner HM, Arnold C, Christ OE, et al. Pharmacokinetics and biotransformation of the antimycotic drug ciclopiroxolamine in animals and man after topical and systemic administration. Arzneimittelforschung. 1981;31(8A):1337-1353.
Gajdošová M, Vetchý D, Muselík J, et al. Bilayer mucoadhesive buccal films with prolonged release of ciclopirox olamine for the treatment of oral candidiasis: In vitro development, ex vivo permeation testing, pharmacokinetic and efficacy study in rabbits. Int J Pharm. 2021;592:120086. doi: 10.1016/j.ijpharm.2020.120086
Rachh MR, Barot BS, Parejiya PB, Shelat PK, Deshpande SS. Development and characterization of ciclopirox olamine loaded buccoadhesive film for treatment of oral candidiasis. 2013;3(1):360-365.
Dhamoon RK, Popli H, Gupta M. Novel Drug Delivery Strategies for the Treatment of Onychomycosis. PNT. 2019;7(1):24-38. doi: 10.2174/2211738507666190228104031
Gupta AK, FRCP(C). Ciclopirox: an overview. Int J Dermatol. 2001;40(5):305-310. doi: 10.1046/j.1365-4362.2001.01156.x
Farr A, Effendy I, Frey Tirri B, et al. Guideline: Vulvovaginal candidosis (AWMF 015/072, level S2k). Mycoses. 2021;64(6):583-602. doi: 10.1111/myc.13248
Subissi A, Monti D, Togni G, Mailland F. Ciclopirox: Recent Nonclinical and Clinical Data Relevant to its Use as a Topical Antimycotic Agent. Drugs. 2010;70(16):2133-2152. doi: 10.2165/11538110-000000000-00000
Nair AB, Singh K, Al-Dhubiab BE, Attimarad M, Harsha S, Alhaider IA. Skin uptake and clearance of ciclopirox following topical application. Biopharmaceutics & Drug Disposition. 2013;34(9):540-549. doi: 10.1002/bdd.1866
Ciclopirox. https://go.drugbank.com/drugs/DB01188. Accessed November 18, 2022.
Pfaller MA. Antifungal Drug Resistance: Mechanisms, Epidemiology, and Consequences for Treatment. Am J Med. 2012;125(1):3-13. doi: 10.1016/j.amjmed.2011.11.001
Minden MD, Hogge DE, Weir SJ, et al. Oral ciclopirox olamine displays biological activity in a phase I study in patients with advanced hematologic malignancies. Am J Hematol. 2014;89(4):363-368. doi: 10.1002/ajh.23640
Gupta AK, Cooper EA. Update in antifungal therapy of dermatophytosis. Mycopathologia. 2008;166(5-6):353-367. doi: 10.1007/s11046-008-9109-0
Gupta AK, Nicol KA. Ciclopirox 1% shampoo for the treatment of seborrheic dermatitis. Int J Dermatol. 2006;45(1):66-69. doi: 10.1111/j.1365-4632.2004.02331.x
Nenoff P, Krüger C, Schaller J, Ginter-Hanselmayer G, Schulte-Beerbühl R, Tietz HJ. Mycology - an update part 2: dermatomycoses: clinical picture and diagnostics. J Dtsch Dermatol Ges. 2014;12(9):749-777. doi: 10.1111/ddg.12420
Dittmar W, Lohaus G. HOE 296, a new antimycotic compound with a broad antimicrobial spectrum. Laboratory results. Arzneimittelforschung. 1973;23(5):670-674.
Danielli LJ, Pippi B, Duarte JA, et al. Antifungal mechanism of action of Schinus lentiscifolius Marchand essential oil and its synergistic effect in vitro with terbinafine and ciclopirox against dermatophytes. Journal of Pharmacy and Pharmacology. 2018;70(9):1216-1227. doi: 10.1111/jphp.12949
Carrillo-Muñoz AJ, Brió S, Alonso R, del Valle O, Santos P, Quindós G. Ciclopiroxolamine: in vitro antifungal activity against clinical yeast isolates. Int J Antimicrob Agents. 2002;20(5):375-379. doi: 10.1016/S0924-8579(02)00206-6
Carrilo-Muñoz AJ, Tur C, Torres J, Seymour AC. In-vitro antifungal activity of sertaconazole, bifonazole, ketoconazole, and miconazole against yeasts of the Candida genus. J Antimicrob Chemother. 1996;37(4):815-819. doi: 10.1093/jac/37.4.815
Harada I, Mitsui K, Uchida K, Yamaguchi H. [The in vitro properties of a new hydroxypyridone antimycotic rilopirox, with special reference to its anti-Candida activity]. Jpn J Antibiot. 1999;52(2):146-152.
Gupta AK, Plott T. Ciclopirox: a broad-spectrum antifungal with antibacterial and anti-inflammatory properties. Int J Dermatol. 2004;43(1):3-8. doi: 10.1111/j.1461-1244.2004.02380.x
Lee REB, Liu TT, Barker KS, Lee RE, Rogers PD. Genome-wide expression profiling of the response to ciclopirox olamine in Candida albicans. J Antimicrob Chemother. 2005;55(5):655-662. doi: 10.1093/jac/dki105
Leem SH, Park JE, Kim IS, Chae JY, Sugino A, Sunwoo Y. The possible mechanism of action of ciclopirox olamine in the yeast Saccharomyces cerevisiae. Mol Cells. 2003;15(1):55-61.
Farinelli S, Greene L. Cell cycle blockers mimosine, ciclopirox, and deferoxamine prevent the death of PC12 cells and postmitotic sympathetic neurons after removal of trophic support. J Neurosci. 1996;16(3):1150-1162. doi: 10.1523/JNEUROSCI.16-03-01150.1996
Almeida B, Sampaio-Marques B, Carvalho J, et al. An atypical active cell death process underlies the fungicidal activity of ciclopirox olamine against the yeast Saccharomyces cerevisiae. FEMS Yeast Research. 2007;7(3):404-412. doi: 10.1111/j.1567-1364.2006.00188.x
Zhou H, Shen T, Luo Y, et al. The antitumor activity of the fungicide ciclopirox. Int J Cancer. 2010;127(10):2467-2477. doi: 10.1002/ijc.25255
Hoffman BD, Hanauske-Abel HM, Flint A, Lalande M. A new class of reversible cell cycle inhibitors. Cytometry. 1991;12(1):26-32. doi: 10.1002/cyto.990120105
Lalande M. A reversible arrest point in the late G1 phase of the mammalian cell cycle. Exp Cell Res. 1990;186(2):332-339. doi: 10.1016/0014-4827(90)90313-y
Luo Y, Zhou H, Liu L, et al. The fungicide ciclopirox inhibits lymphatic endothelial cell tube formation by suppressing VEGFR-3-mediated ERK signaling pathway. Oncogene. 2011;30(18):2098-2107. doi: 10.1038/onc.2010.590
Sundar SS, Ganesan TS. Role of lymphangiogenesis in cancer. J Clin Oncol. 2007;25(27):4298-4307. doi: 10.1200/JCO.2006.07.1092
Wolff EC, Kang KR, Kim YS, Park MH. Posttranslational synthesis of hypusine: evolutionary progression and specificity of the hypusine modification. Amino Acids. 2007;33(2):341-350. doi: 10.1007/s00726-007-0525-0
Kaiser A. Translational control of eIF5A in various diseases. Amino Acids. 2012;42(2):679-684. doi: 10.1007/s00726-011-1042-8
Kim YS, Kang KR, Wolff EC, Bell JK, McPhie P, Park MH. Deoxyhypusine hydroxylase is a Fe(II)-dependent, heat-repeat enzyme: identification of amino acid residues critical for Fe(II) binding and catalysis. J Biol Chem. 2006;281(19):13217-13225. doi: 10.1074/jbc.M601081200
Clement PMJ, Hanauske-Abel HM, Wolff EC, Kleinman HK, Park MH. The antifungal drug ciclopirox inhibits deoxyhypusine and proline hydroxylation, endothelial cell growth and angiogenesis in vitro. Int J Can. 2002;100(4):491-498. doi: 10.1002/ijc.10515
Furukawa T, Naitoh Y, Kohno H, Tokunaga R, Taketani S. Iron deprivation decreases ribonucleotide reductase activity and DNA synthesis. Life Sciences. 1992;50(26):2059-2065. doi: 10.1016/0024-3205(92)90572-7
Eberhard Y, McDermott SP, Wang X, et al. Chelation of intracellular iron with the antifungal agent ciclopirox olamine induces cell death in leukemia and myeloma cells. Blood. 2009;114(14):3064-3073. doi: 10.1182/blood-2009-03-209965
Simcox JA, McClain DA. Iron and Diabetes Risk. Cell Metab. 2013;17(3):329-341. doi: 10.1016/j.cmet.2013.02.007
Papa FR. Endoplasmic Reticulum Stress, Pancreatic β-Cell Degeneration, and Diabetes. Cold Spring Harb Perspect Med. 2012;2(9):a007666. doi: 10.1101/cshperspect.a007666
Mihailidou C, Chatzistamou I, Papavassiliou AG, Kiaris H. Ciclopirox enhances pancreatic islet health by modulating the unfolded protein response in diabetes. Pflugers Arch. 2016;468(11-12):1957-1968. doi: 10.1007/s00424-016-1887-5
Mihailidou C, Chatzistamou I, Papavassiliou AG, Kiaris H. Modulation of Pancreatic Islets’ Function and Survival During Aging Involves the Differential Regulation of Endoplasmic Reticulum Stress by p21 and CHOP. Antioxid Redox Signal. 2017;27(4):185-200. doi: 10.1089/ars.2016.6671
Ashcroft FM, Rorsman P. Diabetes mellitus and the β-cell: the Last Ten Years. Cell. 2012;148(6):1160-1171. doi: 10.1016/j.cell.2012.02.010
Maier B, Ogihara T, Trace AP, et al. The unique hypusine modification of eIF5A promotes islet β cell inflammation and dysfunction in mice. J Clin Invest. 2010;120(6):2156-2170. doi: 10.1172/JCI38924
Hanauske-Abel HM, Saxena D, Palumbo PE, et al. Drug-Induced Reactivation of Apoptosis Abrogates HIV-1 Infection. PLoS One. 2013;8(9):e74414. doi: 10.1371/journal.pone.0074414
Berkhout B, Arts K, Abbink TEM. Ribosomal scanning on the 5′-untranslated region of the human immunodeficiency virus RNA genome. Nucleic Acids Res. 2011;39(12):5232-5244. doi: 10.1093/nar/gkr113
Kim SW, Yoon JS, Lee M, Cho Y. Toward a complete cure for chronic hepatitis B: Novel therapeutic targets for hepatitis B virus. Clin Mol Hepatol. 2022;28(1):17-30. doi: 10.3350/cmh.2021.0093
Kang JA, Kim S, Park M, et al. Ciclopirox inhibits Hepatitis B Virus secretion by blocking capsid assembly. Nat Commun. 2019;10(1):2184. doi: 10.1038/s41467-019-10200-5
Mohebbi A, Ghorbanzadeh T, Naderifar S, Khalaj F, Askari FS, Sammak AS. A fragment-based drug discovery developed on ciclopirox for inhibition of Hepatitis B virus core protein: An in silico study. PLOS ONE. 2023;18(5):e0285941. doi: 10.1371/journal.pone.0285941
Feng H, Hu L, Zhu H, et al. Repurposing antimycotic ciclopirox olamine as a promising anti-ischemic stroke agent. Acta Pharmaceutica Sinica B. 2020;10(3):434-446. doi: 10.1016/j.apsb.2019.08.002
Tan T, Marín-García J, Damle S, Weiss HR. Hypoxia-inducible factor-1 improves inotropic responses of cardiac myocytes in ageing heart without affecting mitochondrial activity. Exp Physiol. 2010;95(6):712-722. doi: 10.1113/expphysiol.2009.051649
Gupta AK, Kohli Y. In vitro susceptibility testing of ciclopirox, terbinafine, ketoconazole and itraconazole against dermatophytes and nondermatophytes, and in vitro evaluation of combination antifungal activity. Br J Dermatol. 2003;149(2):296-305. doi: 10.1046/j.1365-2133.2003.05418.x
Gupta AK, Joseph WS. Ciclopirox 8% nail lacquer in the treatment of onychomycosis of the toenails in the United States. J Am Podiatr Med Assoc. 2000;90(10):495-501. doi: 10.7547/87507315-90-10-495
Zhou H, Shen T, Shang C, et al. Ciclopirox induces autophagy through reactive oxygen species-mediated activation of JNK signaling pathway. Oncotarget. 2014;5(20):10140-10150.
Monti D, Mazzantini D, Tampucci S, et al. Ciclopirox and Efinaconazole Transungual Permeation, Antifungal Activity, and Proficiency To Induce Resistance in Trichophyton rubrum. Antimicrob Agents Chemother. 2019;63(10):e00442-e00519. doi: 10.1128/AAC.00442-19
Conley ZC, Carlson-Banning KM, Carter AG, de la Cova A, Song Y, Zechiedrich L. Sugar and iron: Toward understanding the antibacterial effect of ciclopirox in Escherichia coli. PLoS One. 2019;14(1):e0210547. doi: 10.1371/journal.pone.0210547
Kim Y, Schmidt M, Endo T, Lu D, Carson D, Schmidt-Wolf IGH. Targeting the Wnt/beta-catenin pathway with the antifungal agent ciclopirox olamine in a murine myeloma model. In Vivo. 2011;25(6):887-893.
Rey JB, Osgood AT, Anvari AA. Topical and Device-Based Treatment of Toenail Onychomycosis. Am Fam Physician. 2021;103(3):145-146.
Krasaeath R, Elizondo J. Topical Antifungals for Treatment of Onychomycosis. Am Fam Physician. 2016;94(9):734-734.
Abeck D, Loprox Shampoo Dosing Study Group. Rationale of frequency of use of ciclopirox 1% shampoo in the treatment of seborrheic dermatitis: results of a double-blind, placebo-controlled study comparing the efficacy of once, twice, and three times weekly usage. Int J Dermatol. 2004;43(1):13-16. doi: 10.1111/j.1461-1244.2004.02382.x
Aly R, Maibach HI, Bagatell FK, et al. Ciclopirox olamine lotion 1%: bioequivalence to ciclopirox olamine cream 1% and clinical efficacy in tinea pedis. Clin Ther. 1989;11(3):290-303.
Wajnberg M, Wajnberg A. Doppelblind-Vergleichsstudie mit Ciclopiroxolamin- und Miconazol-Vaginalcreme bei uilvovaginaler Candidose. Mycoses. 1981;24(12):721-730. doi: 10.1111/j.1439-0507.1981.tb01827.x
Gallup E, Plott T, Ciclopirox TS Investigators. A multicenter, open-label study to assess the safety and efficacy of ciclopirox topical suspension 0.77% in the treatment of diaper dermatitis due to Candida albicans. J Drugs Dermatol. 2005;4(1):29-34.
Bernier KM, Morrison LA. Antifungal drug ciclopirox olamine reduces HSV-1 replication and disease in mice. Antiviral Research. 2018;156:102-106. doi: 10.1016/j.antiviral.2018.06.010
Shen T, Huang S. Repositioning the Old Fungicide Ciclopirox for New Medical Uses. CPD. 2016;22(28):4443-4450. doi: 10.2174/1381612822666160530151209
Weir SJ, Wood R, Schorno K, et al. Preclinical Pharmacokinetics of Fosciclopirox, a Novel Treatment of Urothelial Cancers, in Rats and Dogs. J Pharmacol Exp Ther. 2019;370(2):148-159. doi: 10.1124/jpet.119.257972
Shaikh KS. Repurposing ciclopirox for treating multiple forms of cancer: New reports and approaches. JMPAS. 2022;11(2):4727-4733. doi: 10.55522/jmpas.V11I2.2545
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2023 European Journal of Clinical and Experimental Medicine
This work is licensed under a Creative Commons Attribution 4.0 International License.
Our open access policy is in accordance with the Budapest Open Access Initiative (BOAI) definition: this means that articles have free availability on the public Internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from having access to the Internet itself.
All articles are published with free open access under the CC-BY Creative Commons attribution license (the current version is CC-BY, version 4.0). If you submit your paper for publication by the Eur J Clin Exp Med, you agree to have the CC-BY license applied to your work. Under this Open Access license, you, as the author, agree that anyone may download and read the paper for free. In addition, the article may be reused and quoted provided that the original published version is cited. This facilitates freedom in re-use and also ensures that Eur J Clin Exp Med content can be mined without barriers for the research needs.
