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Resistance Mechanism to Histone Deacetylase Inhibitor in Non-small Cell Lung Cancer : 비소세포폐암에서 히스톤탈아세틸화제에 대한 내성 기전
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- Authors
- Advisor
- 방영주
- Major
- 의과대학 의학과
- Issue Date
- 2014-02
- Publisher
- 서울대학교 대학원
- Keywords
- Non-small cell lung cancer ; histone deacetylase inhibitor ; insulin-like growth factor ; resistance mechanism
- Description
- 학위논문 (박사)-- 서울대학교 대학원 : 의학과, 2014. 2. 방영주.
- Abstract
- Background: Histone deacetylase (HDAC), which modulate chromatin structure and gene expression, has attracted attention as a promising therapeutic target for hematologic and solid tumors including non-small cell lung cancer (NSCLC). However, the mechanisms resulting in the resistance to HDAC inhibitors are not yet well-known. In the current study, the involvement of insulin-like growth factor 1 receptor (IGF-1R) signaling was investigated in resistance to HDAC inhibitors in NSCLC.
Material and Methods: Response to vorinostat was tested in a panel of 14 NSCLC cell by MTT assay. Because cells growing in monolayers on standard tissue culture plates (TCPs) could have different response to drug treatment compared with cells growing in vivo, which is three-dimensional (3D), the effects of vorinostat were also tested on the cells cultured in soft agar. After the identification of sensitive and resistant cells, receptor tyrosine kinase (RTK) array was performed to elucidate the culprit growth factor signaling pathway. Western blot analysis or real time quantitative PCR were done to confirm the biochemical changes. The antitumor effects of vorinostat, either alone or in combination with the culprit pathway inhibitor would be evaluated using representative vorinostat-resistant NSCLC cell lines. The antitumor potency of vorinostat, either single or in combination with culprit pathway inhibitor on the growth of NSCLC was evaluated using xenograft tumors of two NSCLC cell lines grown in nude mice.
Results: Based on MTT assay, IC50 values were measured in each cell lines. In relatively resistant cells, vorinostat seemed to induce expression of phosphorylated IGFR (p-IGFR) in dose and time dependent manner. In contrast, expression of p-IGFR in relatively sensitive cells, tended to decrease. Addition of anti-IGF-1R monoclonal antibody dalotuzumab increased cytotoxicity in relatively resistant cells in soft agar colony forming assay. Real-time quantitative PCR revealed significant increases of IGF-2 in the primary and acquired resistant cells. In xenograft model, combined treatment of vorinostat and dalotuzumab significantly delayed tumor growth compared with vehicle only or single agent treatment.
Conclusions: Our results suggested that (a) resistance to vorinostat might be related to activation of IGF-IR and (b) the combination of dalotuzumab could overcome the resistance to vorinostat in vitro and in vivo.
- Language
- English
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