Olaizola Irene, Odriozola-Gimeno Mikel, Olaizola Paula, Caballero-Camino Francisco J, Pastor-Toyos Noelia, Tena-Garitaonaindia Mireia, Lapitz Ainhoa, Val Beatriz, Guimaraes Amanda R, Asensio Maitane, Huici-Izagirre Maider, Rae Colin, de Sancho David, Lopez Xabier, Rodrigues Pedro M, Herraez Elisa, Briz Oscar, Izquierdo-Sanchez Laura, Eleta-Lopez Aitziber, Bittner Alexander M, Martinez-Amesti Ana, Miranda Teresa, Ilyas Sumera I, Braconi Chiara, Perugorria Maria J, Bujanda Luis, Rivilla Iván, Marin Jose J G, Cossío Fernando P, Banales Jesus M
Department of Liver and Gastrointestinal Diseases, Biogipuzkoa Health Research Institute - Donostia University Hospital -, University of the Basque Country (UPV/EHU), Donostia-San Sebastian, Spain.
Department of Organic Chemistry I, Center of Innovation in Advanced Chemistry (ORFEO-CINQA), Faculty of Chemistry, University of the Basque Country (UPV/EHU) & Donostia International Physics Center (DIPC), Donostia-San Sebastian, Spain.
J Hepatol. 2025 May 3. doi: 10.1016/j.jhep.2025.04.034.
BACKGROUND & AIMS: Patients with cholangiocarcinoma (CCA) have poor prognosis. Current cisplatin-based first-line chemotherapy offers limited survival benefit. Cisplatin induces single-strand DNA breaks, activating DNA repair mechanisms that diminish its effectiveness. Here, we present the design, chemical synthesis, and therapeutic evaluation of a new generation of chemotherapeutic agents (Aurkines) with unique polyelectrophilic properties. These agents cause a high frequency of double-strand DNA breaks, bypassing DNA repair, and promoting cancer cell death.
Two novel compounds, Aurkine 16 and Aurkine 18, were designed and evaluated for their antitumor effects in both naïve and cisplatin-resistant CCA cells, cancer-associated fibroblasts, healthy cholangiocytes, and in vivo models.
Aurkines effectively induced double-strand DNA breaks, leading to increased DNA damage and elevated levels of reactive oxygen species, resulting in greater cytotoxicity than cisplatin in CCA cells. Phosphoproteomic and molecular analysis revealed that cisplatin activates DNA repair pathways, while Aurkines primarily induce apoptosis. Importantly, Aurkines also triggered apoptosis in cisplatin-resistant CCA cells and cancer-associated fibroblasts without harming healthy cholangiocytes. Additionally, Aurkines demonstrated cytotoxicity in other cisplatin-resistant cancers, such as breast and ovarian cancer. This tumor selectivity results from reduced uptake, increased efflux, and compact chromatin structure in normal cells, limiting Aurkine-DNA interactions. In vivo, Aurkines inhibited the growth of subcutaneous naïve and cisplatin-resistant CCA tumors, as well as orthotopic tumors in immunocompetent mice, promoting antitumor immune cell recruitment without any adverse events. Transport studies revealed that Aurkines were selectively taken up by OCT1, OCT3, CTR1, and OATP1A2, whereas only CTR1 transported cisplatin.
Aurkines represent promising therapeutic drugs for both naïve and cisplatin-resistant cancers due to their unique polyelectrophilic properties and selective targeting of malignant cells.
This study introduces a novel therapeutic strategy designed to induce frequent double-strand DNA breaks selectively in both naïve and cisplatin-resistant cancer cells, without evident toxic side effects at therapeutic doses. This approach may form the basis for new strategies to overcome the critical challenge of drug resistance in cancer treatment and has the potential to be a breakthrough not only for the treatment of biliary tumors but also for other cancers.
