A novel inhibitor of ADAM17 sensitizes colorectal cancer cells to 5‐Fluorouracil by reversing Notch and epithelial‐mesenchymal transition in vitro and in vivo

Objectives Colorectal cancer is one of the most common malignancies both in men and women. Owing to metastasis and resistance, the prognosis of colorectal cancerCRC patients remains extremely poor with chemotherapy. A disintegrin and metalloproteinase 17 (ADAM17) induces the activation of Notch path...

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Bibliographic Details
Published in:Cell proliferation 2018-10, Vol.51 (5), p.e12480-n/a
Main Authors: Li, Dan‐Dan, Zhao, Chang‐Hao, Ding, Huai‐Wei, Wu, Qiong, Ren, Tian‐Shu, Wang, Jian, Chen, Cong‐Qin, Zhao, Qing‐Chun
Format: Article
Language:English
Subjects:
5-Fluorouracil
A549 Cells
ADAM protein
ADAM17 Protein - antagonists & inhibitors
Antineoplastic Agents - pharmacology
Assaying
Camptothecin - analogs & derivatives
Camptothecin - pharmacology
Cancer
Cell Line, Tumor
Cell migration
Cell Movement - drug effects
Cell proliferation
Cell Proliferation - drug effects
Chemoresistance
Chemosensitization
Chemotherapy
Colorectal cancer
Colorectal carcinoma
Colorectal Neoplasms - drug therapy
Colorectal Neoplasms - metabolism
Epithelial-Mesenchymal Transition - drug effects
Fluorouracil - pharmacology
HeLa Cells
Hep G2 Cells
Humans
Immunofluorescence
In vivo methods and tests
Inhibitors
Invasiveness
Irinotecan
MCF-7 Cells
Mesenchyme
Metastases
Metastasis
Original
Pharmacology
Receptors, Notch - metabolism
Signal Transduction - drug effects
Tumors
Wound healing
Xenografts
Xenotransplantation
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Summary:Objectives Colorectal cancer is one of the most common malignancies both in men and women. Owing to metastasis and resistance, the prognosis of colorectal cancerCRC patients remains extremely poor with chemotherapy. A disintegrin and metalloproteinase 17 (ADAM17) induces the activation of Notch pathway and contributes to the chemoresistance. This study aimed to discover a novel ADAM17 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 ADAM17 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 ADAM17 inhibitor ZLDI‐8 may be a potential chemosensitizer which sensitized CRC cells to 5‐fluorouracil or irinotecan by reversing Notch and EMT pathways.
ISSN:0960-7722
1365-2184
DOI:10.1111/cpr.12480