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.
Triple-negative breast cancer Cisplatin resistance Epithelial-mesenchymal transition Niclosamide
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This work was supported by the National Natural Science Foundation of China (Grant Number: 81172520) and the Technology Innovation Act Plan of the Shanghai Municipal Science and Technology Commission (Grant Numbers: 14411950200 and 14411950201).
Compliance with ethical standards
All experimental xenograft procedures were carried out in compliance with the institutional requirements and approved by the Shanghai Jiao Tong University School of Medicine Committee for the Use and Care of Animals.
Conflicts of interest
M. Pegram served as a consultant advisory board member for Roche/Genentech, Inc. Other authors declare that they have no conflicts of interest in the studies described.
Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest. 2011;121(7):2750–67. doi:10.1172/JCI45014.CrossRefPubMedPubMedCentralGoogle Scholar
von Minckwitz G, Schneeweiss A, Loibl S, Salat C, Denkert C, Rezai M, et al. Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. Lancet Oncol. 2014;15(7):747–56. doi:10.1016/S1470-2045(14)70160-3.CrossRefGoogle Scholar
Silver DP, Richardson AL, Eklund AC, Wang ZC, Szallasi Z, Li Q, et al. Efficacy of neoadjuvant Cisplatin in triple-negative breast cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2010;28(7):1145–53. doi:10.1200/JCO.2009.22.4725.CrossRefGoogle Scholar
Lo Iacono M, Monica V, Vavala T, Gisabella M, Saviozzi S, Bracco E, et al. ATF2 contributes to cisplatin resistance in non-small cell lung cancer and celastrol induces cisplatin resensitization through inhibition of JNK/ATF2 pathway. Int J Cancer. 2015;136(11):2598–609. doi:10.1002/ijc.29302.CrossRefPubMedGoogle Scholar
Wu DW, Lee MC, Hsu NY, Wu TC, Wu JY, Wang YC, et al. FHIT loss confers cisplatin resistance in lung cancer via the AKT/NF-kappaB/Slug-mediated PUMA reduction. Oncogene. 2015;34(29):3882–3. doi:10.1038/onc.2015.203.CrossRefPubMedGoogle Scholar
Wu Y, Ginther C, Kim J, Mosher N, Chung S, Slamon D, et al. Expression of Wnt3 activates Wnt/beta-catenin pathway and promotes EMT-like phenotype in trastuzumab-resistant HER2-overexpressing breast cancer cells. Mol Cancer Res MCR. 2012;10(12):1597–606. doi:10.1158/1541-7786.MCR-12-0155-T.CrossRefPubMedGoogle Scholar
Jin Y, Lu Z, Ding K, Li J, Du X, Chen C, et al. Antineoplastic mechanisms of niclosamide in acute myelogenous leukemia stem cells: inactivation of the NF-kappaB pathway and generation of reactive oxygen species. Cancer Res. 2010;70(6):2516–27. doi:10.1158/0008-5472.CAN-09-3950.CrossRefPubMedGoogle Scholar
Michaelis M, Klassert D, Barth S, Suhan T, Breitling R, Mayer B, et al. Chemoresistance acquisition induces a global shift of expression of aniogenesis-associated genes and increased pro-angogenic activity in neuroblastoma cells. Mol Cancer. 2009;8:80. doi:10.1186/1476-4598-8-80.CrossRefPubMedPubMedCentralGoogle Scholar
Piskareva O, Harvey H, Nolan J, Conlon R, Alcock L, Buckley P, et al. The development of cisplatin resistance in neuroblastoma is accompanied by epithelial to mesenchymal transition in vitro. Cancer Lett. 2015;364(2):142–55. doi:10.1016/j.canlet.2015.05.004.CrossRefPubMedGoogle Scholar
Kurrey NK, Jalgaonkar SP, Joglekar AV, Ghanate AD, Chaskar PD, Doiphode RY, et al. Snail and slug mediate radioresistance and chemoresistance by antagonizing p53-mediated apoptosis and acquiring a stem-like phenotype in ovarian cancer cells. Stem Cells. 2009;27(9):2059–68. doi:10.1002/stem.154.CrossRefPubMedGoogle Scholar
Austin P, Freeman SA, Gray CA, Gold MR, Vogl AW, Andersen RJ, et al. The invasion inhibitor sarasinoside A1 reverses mesenchymal tumor transformation in an E-cadherin-independent manner. Mol Cancer Res MCR. 2013;11(5):530–40. doi:10.1158/1541-7786.MCR-12-0385.CrossRefPubMedGoogle Scholar
Khanim FL, Merrick BA, Giles HV, Jankute M, Jackson JB, Giles LJ, et al. Redeployment-based drug screening identifies the anti-helminthic niclosamide as anti-myeloma therapy that also reduces free light chain production. Blood Cancer J. 2011;1(10):e39. doi:10.1038/bcj.2011.38.CrossRefPubMedPubMedCentralGoogle Scholar
Park SJ, Shin JH, Kang H, Hwang JJ, Cho DH. Niclosamide induces mitochondria fragmentation and promotes both apoptotic and autophagic cell death. BMB Rep. 2011;44(8):517–22.CrossRefPubMedGoogle Scholar
Wang AM, Ku HH, Liang YC, Chen YC, Hwu YM, Yeh TS. The autonomous notch signal pathway is activated by baicalin and baicalein but is suppressed by niclosamide in K562 cells. J Cell Biochem. 2009;106(4):682–92. doi:10.1002/jcb.22065.CrossRefPubMedGoogle Scholar