Anti-cancer effect and gene modulation of ET-743 in human biliary tract carcinoma preclinical models

BMC Cancer

Caterina Peraldo-Neia¹  Giuliana Cavalloni⁵  Marco Soster⁴  Loretta Gammaitoni⁵  Serena Marchiò⁴  Francesco Sassi²  Livio Trusolino²  Andrea Bertotti²  Enzo Medico⁶  Lorenzo Capussotti³  Massimo Aglietta⁵  Francesco Leone⁵ 

[1] University of Turin Medical School, Department of Oncology, IRCCS-Candiolo, Strada provinciale 142, Km 3.95, Candiolo, 10060 Turin, Italy

[2] University of Turin Medical School, Unit of Molecular Pharmacology, IRCCS-Candiolo, Strada provinciale 142, Km 3.95, Candiolo, 10060 Turin, Italy

[3] Department of General Surgery and Surgical Oncology, Ospedale Mauriziano Umberto I, Strada provinciale 142, Km 3.95, Candiolo, 10060 Turin, Italy

[4] Laboratory of Tumor Microenvironment, IRCCS-Candiolo, Strada provinciale 142, Km 3.95, Candiolo, 10060 Turin, Italy

[5] Fondazione del Piemonte per l’Oncologia (FPO), IRCCS-Candiolo, Strada provinciale 142, Km 3.95, Candiolo, 10060 Turin, Italy

[6] Laboratory of Oncogenomics, IRCCS-Candiolo, Italy, Strada provinciale 142, Km 3.95, Candiolo, 10060 Turin, Italy

关键词: Patient-derived xenograft;    Chemotherapy;    Preclinical model;    ET-743;    Biliary tract carcinoma;   

Others  :  1117943
DOI  :  10.1186/1471-2407-14-918

 received in 2014-07-10, accepted in 2014-11-21,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Peraldo-Neia et al.; licensee BioMed Central Ltd.

【 图 表 】

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