Abstract
BackgroundStandard 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.MethodsWe 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.ResultsWe 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.ConclusionsThese 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.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-918) contains supplementary material, which is available to authorized users.
Highlights
Standard chemotherapy in unresectable biliary tract carcinoma (BTC) patients is based on gemcitabine combined with platinum derivatives
ET-743 induces cell cycle perturbation, apoptosis, and activation of proteins involved in DNA damage-repair in biliary tract carcinoma cells in vitro To investigate the capability of ET-743 to interfere with cell growth, BTC cell lines and primary cultures were treated with escalating doses (0.078-10 nM) of ET-743 for 72 hours
Cell cycle status changes and induction of apoptosis by ET-743 were examined on BTC cells after 48 hours of treatment
Summary
Standard chemotherapy in unresectable biliary tract carcinoma (BTC) patients is based on gemcitabine combined with platinum derivatives. Tumor-associated macrophages (TAMs) represent the major class of immune cells within the tumor microenvironment [16] and have been shown to promote tumor proliferation, increase invasiveness and mitigate T cell-mediated cytotoxic antitumor responses [17,18,19]. They are regarded as potential targets in anticancer therapies and, in this context, ET-743 may represent a suitable tool to overcome myelomonocytic cell-mediated exacerbation of the malignant phenotype and immune suppression [20]. Literature reports only the anecdotal case of a BTC patient involved in a phase I study who experienced a complete metabolic response with ET-743 [22]
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