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Introduction

Cholangiocarcinoma (CCA) comprises a heterogeneous group of biliary malignant tumors characterized by dismal prognosis. The first-line treatment for advanced CCA [cisplatin (CisPt) and gemcitabine] is considered palliative due to the high chemoresistance of this cancer, barely impacting on patients’ overall survival. Here, we aimed to design, synthesize and study a new generation of platinum (Pt)-derived chemotherapeutic drugs that produce double-strand DNA breaks (vs classical single-strand breaks induced by CisPt and related compounds) and thus, prevent the development of DNA repair mechanisms in cancer cells.

Aims & Methods

Ten Pt-derivatives (Aurki-Pt#s) were designed and synthesized. Atomic Force Microscopy (AFM) and Transmission Electron Microscopy (TEM) were used to characterize the binding of Aurki-Pt#s to DNA. The antitumoral effect of the two best candidates (Aurki-Pt#1 and #2) was evaluated by measuring the viability of human CCA cells (EGI-1 and HUCCT1), newly generated CisPt-resistant EGI-1 CCA cells, normal human cholangiocytes (NHC) and cancer-associated fibroblasts (CAFs). The DNA damage induced by Aurki-Pt#1 and #2 was assessed using the comet assay. To ascertain the internalization mechanism of Aurki-Pt#1 and #2, substrate competition studies through flow cytometry and accumulation studies using HPLC-MS/MS were carried out. Finally, the effect of Aurki-Pt#1 and #2 was also tested in vivo on a subcutaneous xenograft model of CCA.

Results

Aurki-Pt#s induced double-strand DNA breaks, and the subsequent DNA fragmentation, contrary to CisPt. Aurki-Pt#1 and #2 significantly reduced CCA cell viability. Both compounds triggered increased DNA damage in CCA cells when compared to CisPt, augmenting the reactive oxygen species levels and being more effective when inducing apoptosis in vitro. Additionally, Aurki-Pt#1 and #2 decreased the proliferative capacity of those CCA cells that survived. Importantly, Aurki-Pt#1 and #2 also promoted cell death in CisPt-resistant CCA cells. Moreover, Aurki-Pt#1 and Aurki-Pt#2 caused CCA spheroid shrinkage. On the contrary, Aurki-Pt#1 and #2 did not induce a lethal effect in NHC in culture, but promoted cell cycle arrest. Besides, Aurki-Pt#1 and Aurki-Pt#2 had an impact on the survival of CAFs. Aurki-Pt#1 and #2 were transported into cells through OCT1, OCT3, CTR1 and OATP1A2, which did not transport CisPt. Finally, Aurki-Pt markedly hampered tumor growth on a subcutaneous xenograft model of CCA in comparison with CisPt or vehicle control.

Conclusion

This new generation of Pt-derived chemotherapeutic drugs selectively diminishes CCA cell viability through the induction of double-strand DNA breaks, and has an impact on its tumor microenvironment, representing a promising therapeutic tool for naïve or CisPt-resistant CCA tumors.

NOVEL PLATINUM-BASED CHEMOTHERAPEUTIC AGENTS HALT CHOLANGIOCARCINOMA PROGRESSION THROUGH THE INDUCTION OF DOUBLE-STRAND DNA BREAKS, PREVENTING DNA REPAIR MECHANISMS

Irene Olaizola 1, Mikel Odriozola 2, Maitane Asensio 3, Paula Olaizola 4, Ivan Rivilla 5, Amanda Guimaraes 2, Francisco Javier Caballero Camino 6, Elisa Herráez 3, Oscar Briz 3, Pedro M. Rodrigues 4, María Jesús Perugorria 4, Luis Bujanda Fernández de Piérola 4, Jose J. Garcia-Marin 3, Fernando Cossio 2, Jesús M. Bañales 4

1 Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain

2 Center of Innovation in Advanced Chemistry (ORFEO-CINQA), Faculty of Chemistry, University of the Basque Country (UPV/EHU) and Donostia International Physics Center (DIPC), San Sebastian, Spain

3 Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, Institute of Biomedical Research of Salamanca (IBSAL), University of Salamanca, Salamanca, Spain|||National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto

4 Biodonostia Health Research Institute - Donostia University Hospital -, University of the Basque Country (UPV/EHU), San Sebastian, Spain|||National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto de Salud Carlos III"),

5 Center of Innovation in Advanced Chemistry (ORFEO-CINQA), Faculty of Chemistry, University of the Basque Country (UPV/EHU) and Donostia International Physics Center (DIPC), San Sebastian, Spain|||IKERBASQUE, Basque Foundation for Science, Bilbao, Spain

6 Biodonostia Health Research Institute - Donostia University Hospital -, University of the Basque Country (UPV/EHU), San Sebastian, Spain

Conference

UEG Week Copenhagen 2023

Topics

Hepatobiliary

Submission format

Abstract

Session

PP 07 Liver & biliary (Posters)

Citation

United European Gastroenterology Journal 2023; 11 (Supplement 8)

Published

2023

UEG Mistakes In Articles

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Upper and lower gastrointestinal endoscopy examinations are performed daily as routine diagnostic procedures in a large number of patients with nonspecific indications, such as heartburn, pain, anaemia, bleeding, workup of portal hypertension and so on. Most of the examinations will point to a classic diagnosis (e.g. peptic disease, cancer, variceal management), but sometimes we see patients who've had multiple diagnostic endoscopic procedures in the previous few months with nonconclusive findings. The diagnostic mistakes discussed here are those that sprang to mind based on our endoscopic experience and they are discussed in an evidence-based approach. For therapeutic endoscopic procedures (e.g. ERCP and resections), we present the most important mistakes that are often seen in our practice and have major consequences for the patient. We propose, from our experience, a simple approach to avoid these mistakes.

Mistakes in endoscopy and how to avoid them

Jacques Deviere, Arnaud Lemmers

Topics

Endoscopy

Published

2024

UEG Podcast Episode

UEG Podcast

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Best of UEG Week - DDM Summit with Francisco Real

Francisco X. Real, Julia Mayerle

Topics

Digestive Oncology

Published

2025

UEG Podcast Episode

UEG Podcast

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IBD treatment beyond anti-TNF (Part 1: Present and future)

Pradeep Mundre 1, Ignacio Catalan-Serra 2

1 Bradford Teaching Hospitals NHS trust, Leeds, United Kingdom

2 Norwegian University of Science and Technology, Centre for Molecular Inflammation, Trondheim, Norway

Topics

IBD

Published

2024

UEG Mistakes In Articles

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Endoscopic resection is a widespread, advanced endoscopic technique that can be used to remove superficial lesions in the gastrointestinal tract. Lesions present in all parts of the gastrointestinal tract, such as the oesophagus, stomach, duodenum, small intestine and, above all, colon, can be removed by endoscopic resection. Lesion detection and characterization, the use of appropriate resection devices and methods, and the management of malignant polyps are all important parts of a multistep process that requires training, experience, expertise and a multidisciplinary approach. The diagnostic and therapeutic mistakes discussed here are based on our endoscopic experience. We present the most important mistakes that are often seen in endoscopic resection in our practice and have major consequences for the patient. We propose, from our experience, a simple approach to avoid these mistakes.

Mistakes in endoscopic resection and how to avoid them

Alessandro Repici, Francesco Auriemma

Topics

Endoscopy

Citation

Auriemma F and Repici A. Mistakes in endoscopic resection and how to avoid them. UEG Education 2017; 17: 27–29

Published

2017

UEG Mistakes In Articles

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The introduction and general use of new immunosuppressive agents, including biologic agents and small molecules, has revolutionised the therapeutic management of inflammatory bowel disease (IBD). Such immunosuppression may expose patients to opportunistic infections, which can be challenging to recognise. These infections are crucial due to their association with morbidity or mortality and the challenges regarding effective treatment. New evidence in this field and vaccination strategies for immunosuppressed IBD patients led to updated European Crohn’s and Colitis Organization (ECCO) guidelines in 2021. Here we discuss the errors to avoid when managing the risk of opportunistic infections in IBD patients. The discussion is based on evidence, whenever possible, and our clinical experience.