Effects and mechanisms of novel histone deacetylase inhibitor WJ-6K on lung cancer cell growth and metastasis.

• Main Authors: Mei-YuChen, 陳美瑜
• Other Authors: Yi-Ching Wang
• Format: Others
• Language: en_US
• Published: 2012
• Online Access: http://ndltd.ncl.edu.tw/handle/77208741592235689619

碩士 === 國立成功大學 === 藥理學研究所 === 100 === Background: Overexpression and/or increased activity of histone deacetylases (HDACs) in hematologic and solid malignancies make HDACs a potential therapeutic target for cancer treatment. However, many HDAC inhibitors show serious adverse events in the course of treatment for solid tumors. Purpose: To evaluate the antitumor effects and toxicity of novel HDAC inhibitors, several candidate compounds were examined by in vitro and in vivo models of human lung cancer. Methodology/Results: HDAC inhibition was examined by in vitro HDAC activity assay and western blot of acetylated histone and non-histone proteins. The cytotoxicity effect was examined in five human lung cancer cell lines. The antiproliferatative mechanisms were investigated by flow cytometric cell cycle analysis, apoptosis assay, and repair gene expression assay in cells treated with HDAC inhibitor along or in combination with cisplatin. Mice with A549 tumor xenograft were used to evaluate effects on tumor growth and tumor metastasis. Over 500 candidate compounds were screened by in vitro HDAC activity assay to search for potent HDAC inhibitors. We found that novel HDAC inhibitor, WJ-6K showed HDAC activity inhibition ability better or comparable to FDA-approved HDAC inhibitor SAHA and led to increased HDAC target protein acetylation in lung cancer cells. WJ-6K showed significant cytotoxicity in various lung cancer cell lines without affecting normal lung cell IMR90 at the dose range examined. WJ-6K led to cancer cell death through induction of cell cycle G2/M arrest and mitochondria-mediated apoptosis. Combined treatment of WJ-6K and conventional chemotherapy agent, cisplatin showed synergistic cytotoxicity in lung cancer cells including the cisplatin-resistant cell line H1435 through impairment of DNA damage repair. We further confirmed that WJ-6K was more effective than SAHA in inhibition of tumor growth in A549 xenograft animal model without significant side effects. Using trans-well invasion assays, we found that WJ-6K inhibited cell invasion in A549 at non-cytotoxic doses. We further demonstrated that WJ-6K pre-treatment significantly suppressed A549 metastases to lungs by experimental metastasis assay in mice. Conclusions: Our findings suggest that WJ-6K is a novel potent HDAC inhibitor which suppresses tumor growth and metastasis in lung cancer model, and can potentially be used for lung cancer therapy.