Abstract
Abstract We have synthesized new 32 derivatives of podophyllotoxin and screened candidate showed anti-cancer effect. Among these derivatives, we found beta-Apopicropodophyllin (APP) is candidate derivative inducing cell death against non-small cell lung cancer (NSCLC) cell lines: A549, NCI-1299 and NCI-460 (IC50 values =16.9, 13.1 and 17.1 nM, respectively). We also analyzed MOA (mode of action) of APP and found APP induced cell death via various mechanisms. Firstly, APP inhibits the polymerization of microtubule and induces G2/M phase arrest as well as DNA damage. APP treatment induces expressions of mitosis-related proteins, phospho-ATM, γ-H2AX and p21. Next, the intrinsic and extrinsic apoptotic pathways by APP are activated as shown in the activations of caspase-3, -8 and -9. APP also induces pro-apoptotic ER stress signaling pathway as indicated by elevated expression levels of BiP, phospo-eIF2α, CHOP and ATF4. Additionally, APP also showed radiosensitizer function. Combination of APP and gamma-ionizing radiation (IR) enhanced apoptotic cell death of NSCLC cell via amplification of ER stress. Taken together, these results implied APP might be a potent anti-cancer drug candidate inducing microtubule disruption, DNA damage, cell cycle arrest and ER stress. Citation Format: Ju Yeon Kim, Jeong Hyun Cho, Sang-Gu Hwang, Jie-Young Song, EunAh Lee, Hong-Duck Um, Jong Kuk Park. Beta-Apopicropodophyllin, a derivative of podophyllotoxin, has a function as anticancer drug and radiosenstizer against non-small cell lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3197.
Published Version
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