Natural podophyllotoxin analog 4DPG attenuates EMT and colorectal cancer progression via activation of checkpoint kinase 2

Abstract Epithelial–mesenchymal transition (EMT) is critical for the metastatic dissemination of cancer cells and contributes to drug resistance. In this study, we observed that epithelial colorectal (CRC) transiently exposed 5-fluorouracil (5-FU) (a chemotherapeutic CRC) as well 5-FU-resistant (5-FU-R) develop EMT characters evidenced by activation Vimentin augmented invasive properties. On other hand, 4DPG (4′-demethyl-deoxypodophyllotoxin glucoside), a natural podophyllotoxin analog attenuates invadopodia formation abilities HCT-116/5-FU-R SW-620/5-FU-R cells. Treatment with restrains phosphorylation (Ser38) in 5-FU-R cells, along downregulation mesenchymal markers Twist1 MMP-2 while augmenting expression E-cadherin TIMP-1. Moreover, boosts tumor-suppressor protein, checkpoint kinase 2 (Chk2) via at Thr68 dose-dependent manner Mechanistically, SiRNA-mediated silencing Chk2, treatment Chk2-specific small-molecule inhibitor (PV1019), divulges represses Chk2-dependent manner. Furthermore, immunoprecipitation analysis unveiled prevents complex between p53 resulting rescue its nuclear localization aggressive addition, confers suitable pharmacokinetic properties strongly abrogates tumor growth, polyps formation, lung metastasis an orthotopic rat carcinoma model. conclusion, our findings demonstrate targeted antitumor/anti-metastatic pharmacological lead compound circumvent EMT-associated resistance suggest clinical benefits cancers.