Reference - Detail
|Author||Peraldo-Neia C, Cavalloni G, Soster M, Gammaitoni L, Marchiò S, Sassi F, Trusolino L, Bertotti A, Medico E, Capussotti L, Aglietta M, Leone F.|
|Title||Anti-cancer effect and gene modulation of ET-743 in human biliary tract carcinoma preclinical models.|
BACKGROUND:Standard chemotherapy in unresectable biliary tract carcinoma (BTC) patients is based on gemcitabine combined with platinum derivatives. However, primary or acquired resistance is inevitable and no second-line chemotherapy is demonstrated to be effective. Thus, there is an urgent need to identify new alternative (chemo)therapy approaches.
METHODS:We evaluated the mechanism of action of ET-743 in preclinical models of BTC. Six BTC cell lines (TFK-1, EGI-1, TGBC1, WITT, KMCH, HuH28), two primary cell cultures derived from BTC patients, the EGI-1 and a new established BTC patient-derived xenografts, were used as preclinical models to investigate the anti-tumor activity of ET-743 in vitro and in vivo. Gene expression profiling was also analyzed upon ET-743 treatment in in vivo models.
RESULTS:We found that ET-743 inhibited cell growth of BTC cell lines and primary cultures (IC50 ranging from 0.37 to 3.08 nM) preferentially inducing apoptosis and activation of the complex DNA damage-repair proteins (p-ATM, p-p53 and p-Histone H2A.x) in vitro. In EGI-1 and patient-derived xenografts, ET-743 induced tumor growth delay and reduction of vasculogenesis. In vivo ET-743 induced a deregulation of genes involved in cell adhesion, stress-related response, and in pathways involved in cholangiocarcinogenesis, such as the IL-6, Sonic Hedgehog and Wnt signaling pathways.
CONCLUSIONS:These results suggest that ET-743 could represent an alternative chemotherapy for BTC treatment and encourage the development of clinical trials in BTC patients resistant to standard chemotherapy.
|MeSH||Animals Antineoplastic Agents, Alkylating / pharmacology* Apoptosis / drug effects Ataxia Telangiectasia Mutated Proteins / metabolism Biliary Tract Neoplasms / blood supply Biliary Tract Neoplasms / drug therapy* Biliary Tract Neoplasms / genetics Cell Adhesion / genetics Cell Line, Tumor Cell Proliferation / drug effects Cell Transformation, Neoplastic / genetics DNA Repair / drug effects Dioxoles / pharmacology* Drug Screening Assays, Antitumor Female Gene Expression Regulation, Neoplastic / drug effects Hedgehog Proteins / genetics Hedgehog Proteins / metabolism Histones / metabolism Humans Interleukin-6 / genetics Mice Mice, Inbred NOD Neovascularization, Pathologic / drug therapy Phosphorylation Tetrahydroisoquinolines / pharmacology* Trabectedin Tumor Suppressor Protein p53 / metabolism Wnt Signaling Pathway / drug effects|
|Human and Animal Cells|