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A novel anti-cancer role of beta-apopicropodophyllin against non-small cell lung cancer cells

Authors
Kim, Ju YeonCho, Jeong HyunChoi, Jong-RyooShin, Hyun-JinSong, Jie-YoungHwang, Sang-GuUm, Hong-DuckDo Yoo, YoungKim, JoonPark, Jong Kuk
Issue Date
15-10월-2018
Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
Keywords
beta-apopicropodophyllin; Podophyllotoxin derivatives; Anti-cancer drug; Drug repositioning; Non-small cell lung cancer cells
Citation
TOXICOLOGY AND APPLIED PHARMACOLOGY, v.357, pp.39 - 49
Indexed
SCIE
SCOPUS
Journal Title
TOXICOLOGY AND APPLIED PHARMACOLOGY
Volume
357
Start Page
39
End Page
49
URI
https://scholar.korea.ac.kr/handle/2021.sw.korea/72475
DOI
10.1016/j.taap.2018.08.022
ISSN
0041-008X
Abstract
We previously reported that podophyllotoxin acetate (PA) inhibits the growth and proliferation of non-small cell lung cancer (NSCLC) cells and also makes them more sensitive to radiation and chemotherapeutic agents. In an attempt to enhance PA activity, we synthesized 34 derivatives based on podophyllotoxin (PPT). Screening of the derivative compounds for anti-cancer activity against NSCLC led to the identification of beta-apopicropodophyllin (APP) as a strong anti-cancer agent. In addition to its role as an immunosuppressive regulator of the T-cell mediated immune response, the compound additionally showed anti-cancer activity against A549, NCI-H1299 and NCI-460 cell lines with IC50 values of 16.9, 13.1 and 17.1 nM, respectively. The intracellular mechanisms underlying the effects of APP were additionally examined. APP treatment caused disruption of microtubule polymerization and DNA damage, which led to cell cycle arrest, as evident from accumulation of phospho-CHK2, p21, and phospho-Cdc2. Moreover, APP stimulated the pro-apoptotic ER stress signaling pathway, indicated by elevated levels of BiP, phospho-PERK, phospho-eIF2 alpha, CHOP and ATF4. We further observed activation of caspase-3, -8 and -9, providing evidence that both intrinsic and extrinsic apoptotic pathways were triggered. In vivo, APP inhibited tumor growth of NSCLC xenografts in nude mice by promoting apoptosis. Our results collectively support a novel role of APP as an anticancer agent that evokes apoptosis by inducing microtubule disruption, DNA damage, cell cycle arrest and ER stress.
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