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Anti-cancer Effects of HNHA and Lenvatinib by the Suppression of EMT-Mediated Drug Resistance in Cancer Stem Cells

Authors
 Yong Sang Lee  ;  Seok-Mo Kim  ;  Bup-Woo Kim  ;  Ho Jin Chang  ;  Soo Young Kim  ;  Cheong Soo Park  ;  Ki Cheong Park  ;  Hang-Seok Chang 
Citation
 Neoplasia, Vol.20(2) : 197-206, 2018 
Journal Title
 Neoplasia 
ISSN
 1522-8002 
Issue Date
2018
Abstract
Anaplastic thyroid cancer (ATC) constitutes less than 2% of total thyroid cancers but accounts for 20-40% of thyroid cancer-related deaths. Cancer stem cell drug resistance represents a primary factor hindering treatment. This study aimed to develop targeted agents against thyroid malignancy, focusing on individual and synergistic effects of HNHA (histone deacetylase), lenvatinib (FGFR), and sorafenib (tyrosine kinase) inhibitors. Patients with biochemically and histologically proven papillary thyroid cancer (PTC) and ATC were included. Cell samples were obtained from patients at the Thyroid Cancer Center, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea. PTC and ATC cells were treated with lenvatinib or sorafenib, alone or in combination with HNHA. Tumor-bearing mice (10/group) were administered 10 mg/kg lenvatinib (p.o.) or 40 mg/kg sorafenib (p.o.), alone or in combination with 25 mg/kg HNHA (i.p.) once every three days. Gene expression in patient-derived PTC and ATC cells was compared using a microarray approach. Cellular apoptosis and proliferation were examined by immunohistochemistry and MTT assays. Tumor volume and cell properties were examined in the mouse xenograft model. HNHA-lenvatinib combined treatment induced markers of cell cycle arrest and apoptosis and suppressed anti-apoptosis markers, epithelial-mesenchymal transition (EMT), and the FGFR signaling pathway. Combined treatment induced significant tumor shrinkage in the xenograft model. HNHA-lenvatinib combination treatment thus blocked the FGFR signaling pathway, which is important for EMT. Treatment with HNHA-lenvatinib combination was more effective than either agent alone or sorafenib-HNHA combination. These findings have implications for ATC treatment by preventing drug resistance in cancer stem cells.
Files in This Item:
T201800570.pdf Download
DOI
10.1016/j.neo.2017.12.003
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Bup Woo(김법우) ORCID logo https://orcid.org/0000-0002-1342-9055
Kim, Seok Mo(김석모) ORCID logo https://orcid.org/0000-0001-8070-0573
Kim, Soo Young(김수영) ORCID logo https://orcid.org/0000-0002-8919-3456
Park, Ki Cheong(박기청) ORCID logo https://orcid.org/0000-0002-3435-3985
Park, Cheong Soo(박정수)
Lee, Yong Sang(이용상) ORCID logo https://orcid.org/0000-0002-8234-8718
Chang, Hang Seok(장항석) ORCID logo https://orcid.org/0000-0002-5162-103X
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/162070
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