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A Novel Synthetic Derivative of Deguelin, SH-174, Exhibits Anti-cancer Activities Against Non-small-cell Lung Cancer Cells
새로운 deguelin 합성 유도체인 SH-174의 비소세포성 폐암세포에서의 항암 활성 연구

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Authors
김준용
Advisor
김규원
Major
융합과학기술대학원 분자의학 및 바이오제약학과
Issue Date
2016
Publisher
서울대학교 융합과학기술대학원
Keywords
non-small-cell lung cancerNSCLCdeguelinanti-cancer drugapoptosishypoxiaAMPK-mTORC1
Description
학위논문 (석사)-- 서울대학교 융합과학기술대학원 : 융합과학기술대학원 분자의학 및 바이오제약학과, 2016. 2. 김규원.
Abstract
The naturally occurring rotenoid, deguelin, has been studied to have a strong anti-cancer efficacy in various types of cancer for more than a decade. However, its intolerable toxicity at therapeutic dose and light-labile physical property deterred its development to be a clinical drug of use. Here, I report that SH-174, a novel synthetic derivative of deguelin, has a strong anti-cancer activity against several non-small-cell lung cancer (NSCLC) cells while having no or a less toxicity to human non-cancerous normal cells (e.g. BEAS-2B, ARPE-19, and HUVEC) than deguelin has. Several NSCLC cell lines were treated with or without SH-174 and subject to MTT assay, colony formation assay, and apoptosis assay
all of which treated with SH-174 exhibited significant inhibited results on the proliferation and survival of those cancer cells. Moreover, SH-174 reduced the ability of cancer cells to adapt to and survive under hypoxic cancer microenvironment by downregulating phosphorylation of Akt and MEK1/2, as well as HIF-1α protein level. To elucidate the target of oncogenic signaling in NSCLC cells by SH-174, I examined the AMPK-mTORC1 signaling axis which is harnessed by cancers for their rapid proliferation and survival. As a result, SH-174 induced the phosphorylation of AMPKα at Thr172, resulting in the inhibition of mTORC1 activity on cellular proliferation. This suggests SH-174 blocks the unchecked proliferation of cancer cells by modulating AMPK-mTORC1 signaling pathway. Thus, SH-174 is a new promising candidate for lung cancer therapy and further in vivo studies in animals are warranted.
Language
English
URI
http://hdl.handle.net/10371/133385
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Graduate School of Convergence Science and Technology (융합과학기술대학원)Molecular Medicine & Biopharmaceutical Sciences(분자의학 및 바이오제약학과)Theses (Master's Degree_분자의학 및 바이오제약학과)
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