title: Multi-targeted therapy of cancer by niclosamide: A new application for an old drug.
abstract: The rapid development of new anticancer drugs that are safe and effective is a common goal shared by basic scientists, clinicians and patients. The current review discusses one such agent, namely niclosamide, which has been used in the clinic for the treatment of intestinal parasite infections. Recent studies repeatedly identified niclosamide as a potential anticancer agent by various high-throughput screening campaigns. Niclosamide not only inhibits the Wnt/β-catenin, mTORC1, STAT3, NF-κB and Notch signaling pathways, but also targets mitochondria in cancer cells to induce cell cycle arrest, growth inhibition and apoptosis. A number of studies have established the anticancer activities of niclosamide in both in vitro and in vivo models. Moreover, the inhibitory effects of niclosamide on cancer stem cells provide further evidence for its consideration as a promising drug for cancer therapy. This article reviews various aspects of niclosamide as they relate to its efficacy against cancer and associated molecular mechanisms.
authors.affiliation: Drug Discovery Division, Southern Research Institute, Birmingham, AL, United States. Electronic address: y.li@southernresearch.org.
authors.forename: Yonghe
authors.initials: Y
authors.lastname: Li
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, United States.
authors.forename: Pui-Kai
authors.initials: PK
authors.lastname: Li
authors.affiliation: Drug Development Division, Southern Research Institute, Birmingham, AL, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Roberts
authors.affiliation: Department of Gynecologic Oncology, The University of Alabama at Birmingham, Birmingham, AL, United States.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Arend
authors.affiliation: Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL, United States.
authors.forename: Rajeev S
authors.initials: RS
authors.lastname: Samant
authors.affiliation: Department of Radiation Oncology, The University of Alabama at Birmingham, Birmingham, AL, United States.
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Buchsbaum
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009534:Niclosamide / Q000494:pharmacology* / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D009534:Niclosamide
keywords: Cancer stem cells; Drug discovery; FDA-approved drug; Multi-targeted therapy; Niclosamide
references.citation: Curr Med Chem. 2013;20(33):4095-101
references.pmid: 23931281
references.citation: BMB Rep. 2011 Aug;44(8):517-22
references.pmid: 21871175
references.citation: Chem Biol Drug Des. 2012 Mar;79(3):235-8
references.pmid: 22145602
references.citation: Nat Rev Cancer. 2006 Oct;6(10):813-23
references.pmid: 16990858
references.citation: Cell. 2012 Jun 8;149(6):1192-205
references.pmid: 22682243
references.citation: Cell. 1994 Mar 11;76(5):821-8
references.pmid: 7510216
references.citation: J Biol Chem. 2013 Dec 13;288(50):35769-80
references.pmid: 24174532
references.citation: Annu Rev Biophys. 2013;42:443-68
references.pmid: 23495970
references.citation: Nat Rev Mol Cell Biol. 2013 Mar;14(3):133-9
references.pmid: 23361334
references.citation: Clin Cancer Res. 2007 Jul 15;13(14):4042-5
references.pmid: 17634527
references.citation: Angew Chem Int Ed Engl. 2013 Mar 4;52(10):2744-92
references.pmid: 23418026
references.citation: J Biol Chem. 2012 May 18;287(21):17530-17545
references.pmid: 22474287
references.citation: EMBO Rep. 2004 Sep;5(9):837-42
references.pmid: 15470377
references.citation: Clin Cancer Res. 2010 Jun 15;16(12):3141-52
references.pmid: 20530696
references.citation: Leukemia. 2008 Apr;22(4):686-707
references.pmid: 18337767
references.citation: Clin Cancer Res. 2013 Aug 1;19(15):4124-36
references.pmid: 23908450
references.citation: Mol Biol Cell. 2011 Sep;22(18):3344-54
references.pmid: 21795396
references.citation: J Cell Mol Med. 2009 Aug;13(8B):2236-2252
references.pmid: 18681906
references.citation: Science. 1994 Apr 1;264(5155):95-8
references.pmid: 8140422
references.citation: PLoS One. 2009 Sep 22;4(9):e7124
references.pmid: 19771169
references.citation: Nat Med. 2001 Aug;7(8):954-60
references.pmid: 11479629
references.citation: PLoS One. 2013 Sep 18;8(9):e74538
references.pmid: 24058587
references.citation: Nature. 2007 Aug 9;448(7154):645-6
references.pmid: 17687303
references.citation: Cell. 2009 Aug 21;138(4):645-659
references.pmid: 19682730
references.citation: PLoS One. 2011;6(12):e29290
references.pmid: 22195040
references.citation: Chin J Cancer. 2012 Apr;31(4):178-84
references.pmid: 22237038
references.citation: Cell. 2000 Oct 13;103(2):311-20
references.pmid: 11057903
references.citation: Cell Signal. 2013 Apr;25(4):961-9
references.pmid: 23333246
references.citation: J Cell Biol. 2012 Aug 6;198(3):281-93
references.pmid: 22869594
references.citation: Oncogene. 2006 Aug 7;25(34):4812-30
references.pmid: 16892093
references.citation: J Biomed Biotechnol. 2012;2012:950658
references.pmid: 23251084
references.citation: PLoS One. 2013 Sep 03;8(9):e74670
references.pmid: 24019973
references.citation: Cancer Res. 2008 Apr 1;68(7):2419-26
references.pmid: 18381450
references.citation: Clin Cancer Res. 1997 Dec;3(12 Pt 1):2309-16
references.pmid: 9815629
references.citation: Mol Cancer Ther. 2014 Apr;13(4):800-11
references.pmid: 24552774
references.citation: Mol Cell Biol. 1997 Aug;17(8):4677-86
references.pmid: 9234724
references.citation: Mol Cancer Ther. 2013 Oct;12(10):2200-12
references.pmid: 23894143
references.citation: Nat Rev Cancer. 2009 Nov;9(11):798-809
references.pmid: 19851315
references.citation: Cancer Res. 2005 Jul 15;65(14):6207-19
references.pmid: 16024622
references.citation: Gastroenterology. 2006 Nov;131(5):1486-500
references.pmid: 17101323
references.citation: Cell Stem Cell. 2007 Nov;1(5):555-67
references.pmid: 18371393
references.citation: Cancer Cell. 2007 Jul;12(1):9-22
references.pmid: 17613433
references.citation: Clin Chem. 1999 Jan;45(1):7-17
references.pmid: 9895331
references.citation: Clin Cancer Res. 2010 Jun 15;16(12):3130-40
references.pmid: 20530699
references.citation: Mol Cancer Ther. 2012 Aug;11(8):1703-12
references.pmid: 22576131
references.citation: Profiles Drug Subst Excip Relat Methodol. 2005;32:67-96
references.pmid: 22469082
references.citation: Br J Cancer. 2012 Jan 3;106(1):99-106
references.pmid: 22215106
references.citation: Nat Rev Clin Oncol. 2010 Apr;7(4):209-19
references.pmid: 20234352
references.citation: ACS Med Chem Lett. 2010 Sep 07;1(9):454-9
references.pmid: 24900231
references.citation: Nat Rev Cancer. 2013 Jan;13(1):11-26
references.pmid: 23258168
references.citation: Nature. 2001 Jul 19;412(6844):346-51
references.pmid: 11460167
references.citation: Biochemistry. 2009 Nov 3;48(43):10267-74
references.pmid: 19772353
references.citation: Nat Rev Cancer. 2008 Oct;8(10):755-68
references.pmid: 18784658
references.citation: ACS Med Chem Lett. 2013 Feb 14;4(2):180-185
references.pmid: 23459613
references.citation: Clin Cancer Res. 2003 Sep 1;9(10 Pt 1):3731-41
references.pmid: 14506165
references.citation: Science. 1994 Jun 3;264(5164):1415-21
references.pmid: 8197455
references.citation: Cancer Res. 2010 Mar 15;70(6):2516-27
references.pmid: 20215516
references.citation: Curr Opin Genet Dev. 2008 Feb;18(1):19-26
references.pmid: 18440219
references.citation: Gastroenterology. 2002 Nov;123(5):1478-84
references.pmid: 12404222
references.citation: J Cell Biochem. 2009 Mar 1;106(4):682-92
references.pmid: 19160421
references.citation: J Biol Chem. 1999 Apr 9;274(15):10641-8
references.pmid: 10187861
references.citation: J Antibiot (Tokyo). 1974 Nov;27(11):814-21
references.pmid: 4452657
references.citation: Nature. 2001 Nov 1;414(6859):105-11
references.pmid: 11689955
references.citation: Nature. 2006 May 25;441(7092):431-6
references.pmid: 16724054
references.citation: Pharmacol Ther. 1982;19(2):245-95
references.pmid: 6763710
references.citation: Cancer Treat Rev. 2012 Oct;38(6):589-98
references.pmid: 22469558
references.citation: EMBO J. 2012 Jun 13;31(12):2737-46
references.pmid: 22617421
references.citation: Nat Rev Clin Oncol. 2011 Feb;8(2):97-106
references.pmid: 21151206
references.citation: Cancer Res. 2007 Mar 1;67(5):1879-82
references.pmid: 17332312
references.citation: J Natl Cancer Inst. 2011 Jul 6;103(13):1018-36
references.pmid: 21685359
references.citation: Blood Cancer J. 2011 Oct;1(10):e39
references.pmid: 22829072
references.citation: Neoplasma. 2002;49(6):349-55
references.pmid: 12584581
references.citation: Mol Cancer Ther. 2014 Mar;13(3):606-16
references.pmid: 24362463
references.citation: Cancer Res. 2011 Jun 15;71(12):4172-82
references.pmid: 21531761
references.citation: Oncogene. 2008 Sep 1;27(38):5124-31
references.pmid: 18758481
references.citation: Bioorg Med Chem Lett. 2013 Apr 1;23(7):2187-91
references.pmid: 23453073