ArticleJournal of hepatology2025
New platinum derivatives selectively cause double-strand DNA breaks and death in naïve and cisplatin-resistant cholangiocarcinomas.
Article in Journal of hepatology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- Engineered nanodendritic sonosensitizers empower sonodynamic-elicited ferroptosis and PANoptosis against platinum-resistant breast cancer.Materials today. Bio · 2026Article
- Prognostic, Predictive, and Clinical Relevance of DNA Damage Repair Alterations in Biliary Tract Cancers.Cancers · 2026Review
- Sijunzi Decoction Reverses Metabolic Adaptation and Induces Ferroptosis in Cisplatin-Resistant Non-small Cell Lung Cancer: An Integrative Metabolomics-Pharmacology Analysis.Current medical science · 2026Article
- Homoisoflavanone Delays Colorectal Cancer Progression via DNA Damage-Induced Mitochondrial Apoptosis and Parthanatos-Like Cell Death.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- The Art of Domesticating Proteins: How Cancer Cells Adapt to Therapeutic and Environmental Stressors.International journal of molecular sciences · 2026Review
- Computational Analysis of a Next-Generation Platinum-Based Chemotherapies that Induce DNA Double-Strand Breaks.Journal of chemical information and modeling · 2026Article
- Cholangiocarcinoma 2026: status quo, unmet needs and priorities.Nature reviews. Gastroenterology & hepatology · 2026Review
- Cuproptosis: a novel therapeutic mechanism in lung cancer.Cancer cell international · 2025Review
Corrections and comments
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Authors and funding
30 authors.
Funding
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Abstract
BACKGROUND &
aimsPatients 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.
methodsTwo 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.
resultsAurkines 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.
conclusionsAurkines represent promising therapeutic drugs for both naïve and cisplatin-resistant cancers due to their unique polyelectrophilic properties and selective targeting of malignant cells. IMPACT AND IMPLICATIONS: 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.
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