A histone deacetylase inhibitor YCW1 with antitumor and antimetastasis properties enhances cisplatin activity against non-small cell lung cancer in preclinical studies

Wei-Jan Huang; Yen-An Tang; Mei-Yu Chen; Ying-Jan Wang; Fu-Han Hu; Tseng-Wei Wang; Shi-Wei Chao; Hui-Wen Chiu; Ya-Ling Yeh; Hsin-Yi Chang; Hsueh-Fen Juan; Pinpin Lin; Yi-Ching Wang

doi:10.1016/j.canlet.2013.12.016

A histone deacetylase inhibitor YCW1 with antitumor and antimetastasis properties enhances cisplatin activity against non-small cell lung cancer in preclinical studies

Cancer Lett. 2014 Apr 28;346(1):84-93. doi: 10.1016/j.canlet.2013.12.016. Epub 2013 Dec 16.

Authors

Wei-Jan Huang¹, Yen-An Tang², Mei-Yu Chen³, Ying-Jan Wang⁴, Fu-Han Hu³, Tseng-Wei Wang⁵, Shi-Wei Chao¹, Hui-Wen Chiu⁴, Ya-Ling Yeh⁴, Hsin-Yi Chang⁶, Hsueh-Fen Juan⁶, Pinpin Lin⁷, Yi-Ching Wang⁸

Affiliations

¹ Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei, Taiwan, ROC.
² Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan, ROC.
³ Department of Pharmacology, National Cheng Kung University, Tainan, Taiwan, ROC.
⁴ Department of Environmental and Occupational Health, National Cheng Kung University, Tainan, Taiwan, ROC.
⁵ Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan, Taiwan, ROC.
⁶ Department of Life Science, National Taiwan University, Taipei, Taiwan, ROC.
⁷ Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan, Taiwan, ROC. Electronic address: 950136@nhri.org.tw.
⁸ Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan, ROC; Department of Pharmacology, National Cheng Kung University, Tainan, Taiwan, ROC. Electronic address: ycw5798@mail.ncku.edu.tw.

PMID: 24355296
DOI: 10.1016/j.canlet.2013.12.016

Abstract

Many histone deacetylase (HDAC) inhibitors show limited therapeutic effects for solid tumors. Here, we develop a novel HDAC inhibitor YCW1 and verify the combination effect of YCW1 and cisplatin in lung cancer pre-clinical models. YCW1 exerted cancer-specific cytotoxicity via mitochondria-mediated apoptosis. YCW1 and cisplatin showed synergistic anti-tumor effects through impairment of DNA damage repair. YCW1 inhibited tumor growth in lung orthotopic and subcutaneously implanted xenograft models. YCW1 significantly suppressed lung metastases via inhibition of focal adhesion complex. Our findings suggested that YCW1 is a potential HDAC inhibitor for lung cancer treatment as single and in combination regimens with cisplatin.

Keywords: Apoptosis; Cisplatin; Histone deacetylase inhibitor; Metastasis; Non-small cell lung cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
Azides / administration & dosage*
Carcinoma, Non-Small-Cell Lung / drug therapy*
Cisplatin / administration & dosage*
Drug Synergism
Histone Deacetylase Inhibitors / administration & dosage*
Humans
Hydroxamic Acids / administration & dosage*
Lung Neoplasms / drug therapy*
Male
Mice, Inbred BALB C
Reverse Transcriptase Polymerase Chain Reaction
Xenograft Model Antitumor Assays

Substances

Azides
Histone Deacetylase Inhibitors
Hydroxamic Acids
octanedioic acid (1-(3-azido-5-azidomethylbenzyl)-1H-pyrazol-4-yl)amide hydroxyamide
Cisplatin