Open AccessA novel inhibitor of ADAM 17 sensitizes colorectal cancer cells to 5‐Fluorouracil by reversing Notch and epithelial‐mesenchymal transition in vitro and in vivo
Author(s) -
Li DanDan,
Zhao ChangHao,
Ding HuaiWei,
Wu Qiong,
Ren TianShu,
Wang Jian,
Chen CongQin,
Zhao QingChun
Publication year - 2018
Publication title -
cell proliferation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.647
H-Index - 74
eISSN - 1365-2184
pISSN - 0960-7722
DOI - 10.1111/cpr.12480
Subject(s) - epithelial–mesenchymal transition , cancer research , notch signaling pathway , in vivo , colorectal cancer , mtt assay , metastasis , chemistry , cell growth , biology , cancer , medicine , microbiology and biotechnology , signal transduction , biochemistry
Objectives Colorectal cancer is one of the most common malignancies both in men and women. Owing to metastasis and resistance, the prognosis of colorectal cancer CRC patients remains extremely poor with chemotherapy. A disintegrin and metalloproteinase 17 ( ADAM 17) induces the activation of Notch pathway and contributes to the chemoresistance. This study aimed to discover a novel ADAM 17 inhibitor and investigate the chemosensitization effect. Materials and methods Pharmacophore model, western blot and enzymatic assay were used to discover ZLDI ‐8. Cell proliferation was determined by MTT and colony formation assay. Cell migratory and invasive ability were determined by wound healing scratch and transwell assay. Immunofluorescence images and western blot analysed the expression of Notch or epithelial‐mesenchymal transition ( EMT ) pathway markers. Xenografts were employed to evaluate the chemosensitization effect of ZLDI ‐8 in vivo. Results We found that ZLDI ‐8 cell‐specifically inhibited the proliferation of CRC , and this effect was due to abrogation of ADAM 17 and Notch pathway. Meanwhile, we reported for the first time that ZLDI ‐8 synergistically improved the anti‐tumour and anti‐metastasis activity of 5‐fluorouracil or irinotecan by reversing Notch and EMT pathways. Interestingly, in vivo studies further demonstrated that ZLDI ‐8 promoted the anti‐tumour effect of 5‐fluorouracil through Notch and EMT reversal. Conclusions A novel ADAM 17 inhibitor ZLDI ‐8 may be a potential chemosensitizer which sensitized CRC cells to 5‐fluorouracil or irinotecan by reversing Notch and EMT pathways.