title: Combined niclosamide with cisplatin inhibits epithelial-mesenchymal transition and tumor growth in cisplatin-resistant triple-negative breast cancer.
abstract: Women with triple-negative breast cancer have worse prognosis compared to other breast cancer subtypes. Acquired drug resistance remains to be an important reason influencing triple-negative breast cancer treatment efficacy. A prevailing theory postulates that the cancer resistance and recurrence results from a subpopulation of tumor cells with stemness program, which are often insensitive to cytotoxic drugs such as cisplatin. Recent studies suggested that niclosamide, an anti-helminthic drug, has potential therapeutic activities against breast cancer stem cells, which prompts us to determine its roles on eliminating cisplatin-resistant cancer cells. Hence, we established a stable cisplatin-resistant MDA-MB-231 cell line (231-CR) through continuously exposure to increasing concentrations of cisplatin (5-20 μmol/l). Interestingly, 231-CR exhibited properties associated to epithelial-mesenchymal transition with enhanced invasion, preserved proliferation, increased mammosphere formation, and reduced apoptosis compared to naive MDA-MB-231 sensitive cells (231-CS). Importantly, niclosamide or combination with cisplatin inhibited both 231-CS and 231-CR cell proliferation in vitro. In addition, niclosamide reversed the EMT phenotype of 231-CR by downregulation of snail and vimentin. Mechanistically, niclosamide treatment in combination with or without cisplatin significantly inhibited Akt, ERK, and Src signaling pathways. In vivo study showed that niclosamide or combination with cisplatin could repress the growth of xenografts originated from either 231-CS or 231-CR cells, with prominent suppression of Ki67 expression. These findings suggested that niclosamide might serve as a novel therapeutic strategy, either alone or in combination with cisplatin, for triple-negative breast cancer treatment, especially those resistant to cisplatin.
authors.affiliation: Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiaotong Univerisity School of Medicine, Shanghai, China.
authors.forename: Junjun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiaotong Univerisity School of Medicine, Shanghai, China.
authors.forename: Xiaosong
authors.initials: X
authors.lastname: Chen
authors.affiliation: Stanford Cancer Institute, Stanford University School of Medicine, 265 Campus Drive West, Suite G2021, Stanford, CA, USA.
authors.forename: Toby
authors.initials: T
authors.lastname: Ward
authors.affiliation: Stanford Cancer Institute, Stanford University School of Medicine, 265 Campus Drive West, Suite G2021, Stanford, CA, USA. mpegram@stanford.edu.
authors.forename: Mark
authors.initials: M
authors.lastname: Pegram
authors.affiliation: Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiaotong Univerisity School of Medicine, Shanghai, China. kwshen@medmail.com.cn.
authors.forename: Kunwei
authors.initials: K
authors.lastname: Shen
mesh_terms: D000818:Animals; D000923:Anticestodal Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002945:Cisplatin / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009534:Niclosamide / Q000494:pharmacology*; D015398:Signal Transduction; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000923:Anticestodal Agents; D000970:Antineoplastic Agents; D009534:Niclosamide; D002945:Cisplatin
keywords: Cisplatin resistance; Epithelial-mesenchymal transition; Niclosamide; Triple-negative breast cancer
references.citation: Mol Cancer Ther. 2013 Oct;12(10):2200-12
references.pmid: 23894143
references.citation: Cancer Lett. 2014 Oct 1;352(2):179-86
references.pmid: 25016063
references.citation: Mol Cancer Ther. 2012 Aug;11(8):1703-12
references.pmid: 22576131
references.citation: J Clin Invest. 2011 Jul;121(7):2750-67
references.pmid: 21633166
references.citation: Lancet Oncol. 2014 Jun;15(7):747-56
references.pmid: 24794243
references.citation: N Engl J Med. 2010 Nov 11;363(20):1938-48
references.pmid: 21067385
references.citation: Exp Parasitol. 2008 Apr;118(4):637-40
references.pmid: 18226810
references.citation: J Cell Biochem. 2009 Mar 1;106(4):682-92
references.pmid: 19160421
references.citation: Blood Cancer J. 2011 Oct;1(10):e39
references.pmid: 22829072
references.citation: Int J Cancer. 2015 Jun 1;136(11):2598-609
references.pmid: 25359574
references.citation: BMB Rep. 2011 Aug;44(8):517-22
references.pmid: 21871175
references.citation: Genes Dev. 2012 Jul 1;26(13):1393-408
references.pmid: 22751496
references.citation: BMC Cancer. 2012 Mar 19;12 :91
references.pmid: 22429801
references.citation: J Mammary Gland Biol Neoplasia. 2009 Mar;14(1):29-43
references.pmid: 19242781
references.citation: Cell. 2009 Aug 21;138(4):645-659
references.pmid: 19682730
references.citation: Int J Gynecol Cancer. 2009 Dec;19 Suppl 2:S30-4
references.pmid: 19955911
references.citation: Mol Cancer Res. 2012 Dec;10 (12 ):1597-606
references.pmid: 23071104
references.citation: J Biochem. 2011 Jun;149(6):633-9
references.pmid: 21478191
references.citation: Cancer Res. 2010 Mar 15;70(6):2516-27
references.pmid: 20215516
references.citation: Am Soc Clin Oncol Educ Book. 2015;:e31-9
references.pmid: 25993190
references.citation: Mol Cancer Res. 2013 Oct;11(10 ):1269-78
references.pmid: 23814023
references.citation: J Clin Oncol. 2010 Mar 1;28(7):1145-53
references.pmid: 20100965
references.citation: Cancer Res. 2009 Apr 1;69(7):2887-95
references.pmid: 19276366
references.citation: Cancer Lett. 2015 Aug 10;364(2):142-55
references.pmid: 25960282
references.citation: Mol Cancer. 2009 Sep 29;8:80
references.pmid: 19788758
references.citation: Biomed Pharmacother. 2011 Feb;65(1):40-5
references.pmid: 21177063
references.citation: Oncogene. 2015 Jul;34(29):3882-3
references.pmid: 26179457
references.citation: Mol Cancer Ther. 2014 Apr;13(4):800-11
references.pmid: 24552774
references.citation: Profiles Drug Subst Excip Relat Methodol. 2005;32:67-96
references.pmid: 22469082
references.citation: Gynecol Oncol. 2015 Apr;137(1):143-51
references.pmid: 25579119
references.citation: Cancer Res. 2014 Feb 1;74(3):862-72
references.pmid: 24295734
references.citation: PLoS One. 2011;6(12 ):e29290
references.pmid: 22195040
references.citation: Cancer Lett. 2015 Aug 1;364(1):44-58
references.pmid: 25917568
references.citation: PLoS One. 2013 Sep 18;8(9):e74538
references.pmid: 24058587
references.citation: Mol Cancer Res. 2013 May;11(5):530-40
references.pmid: 23399642
references.citation: Stem Cells. 2009 Sep;27(9):2059-68
references.pmid: 19544473
references.citation: Cell Death Dis. 2014 Jul 17;5:e1336
references.pmid: 25032859
references.citation: Cancer Sci. 2009 Oct;100(10 ):1834-41
references.pmid: 19681904
references.citation: Cancer Res. 2011 Jun 15;71(12 ):4172-82
references.pmid: 21531761
references.citation: Cancer Lett. 2014 Dec 1;355(1):34-45
references.pmid: 25236911
references.citation: Cancer Lett. 2014 Jul 10;349(1):8-14
references.pmid: 24732808