Dataset Information

Novel chemotherapy selectively induces double-strand DNA breaks and death in naïve and Cisplatin-resistant cholangiocarcinoma tumours - total proteomics and phosphoproteomics

ABSTRACT: Background & Aims: Patients with cholangiocarcinoma (CCA) have poor prognosis. Current first-line chemotherapy, including Cisplatin and Gemcitabine, provides limited survival benefits due to the development of chemoresistance. Cisplatin induces single-strand DNA breaks, activating DNA repair mechanisms that diminish its effectiveness. In this study, we present the design, chemical synthesis, and therapeutic evaluation of a new generation of chemotherapeutic agents with unique polyelectrophilic properties, capable of inducing high frequency of double-strand DNA breaks, thereby inhibiting DNA repair and promoting cancer cell death. Methods: Two novel compounds, Aurkine 16 and Aurkine 18, were designed and evaluated for their antitumour effects in both naïve and Cisplatin-resistant CCA cells, cancer-associated fibroblasts (CAFs), healthy cholangiocytes, and xenograft models. Results: Aurkines effectively induced double-strand DNA breaks, leading to increased DNA damage and elevated levels of reactive oxygen species, resulting in greater cytotoxicity compared to Cisplatin in CCA cells. Unlike Cisplatin, Aurkines did not activate key proteins involved in single-strand DNA repair, such as ATR and CHK1 phosphorylation. Importantly, these compounds also triggered apoptosis in Cisplatin-resistant CCA cells and CAFs without harming healthy cholangiocytes. Additionally, Aurkines demonstrated cytotoxicity in other Cisplatin-resistant cancers, such as breast and ovarian cancer. This selective action against malignant cells was attributed to differences in histone deacetylase (HDAC)-dependent DNA packaging between normal and cancer cells. In vivo, Aurkines inhibited the growth of both naïve and Cisplatin-resistant CCA tumours without adverse effects. Transport studies revealed that Aurkines were selectively taken up by transport proteins OCT1, OCT3, CTR1, and OATP1A2, whereas Cisplatin only modestly utilizes CTR1.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

DISEASE(S): Cholangiocarcinoma

SUBMITTER: Mikel Azkargorta

LAB HEAD: Felix Elortza

PROVIDER: PXD061935 | Pride | 2025-11-10

REPOSITORIES: Pride

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			Action	DRS
	250123B_10_S1-C10_1_18801.d.RAW	Raw
	250123B_11_S1-C11_1_18802.d.RAW	Raw
	250123B_12_S1-C12_1_18803.d.RAW	Raw
	250123B_13_S1-D1_1_18804.d.RAW	Raw
	250123B_14_S1-D2_1_18805.d.RAW	Raw

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Publications

New platinum derivatives selectively cause double-strand DNA breaks and death in naïve and cisplatin-resistant cholangiocarcinomas.

Olaizola Irene I Odriozola-Gimeno Mikel M Olaizola Paula P Caballero-Camino Francisco J FJ Pastor-Toyos Noelia N Tena-Garitaonaindia Mireia M Lapitz Ainhoa A Val Beatriz B Guimaraes Amanda R AR Asensio Maitane M Huici-Izagirre Maider M Rae Colin C de Sancho David D Lopez Xabier X Rodrigues Pedro M PM Herraez Elisa E Briz Oscar O Izquierdo-Sanchez Laura L Eleta-Lopez Aitziber A Bittner Alexander M AM Martinez-Amesti Ana A Miranda Teresa T Ilyas Sumera I SI Braconi Chiara C Perugorria Maria J MJ Bujanda Luis L Rivilla Iván I Marin Jose J G JJG Cossío Fernando P FP Banales Jesus M JM

Journal of hepatology 20250503 5

<h4>Background & aims</h4>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-s ...[more]

PMID: 40324694

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Project description:Background & Aims: Cholangiocarcinomas (CCAs), heterogeneous biliary tumors with dismal prognosis, lack accurate early-diagnostic methods, especially important for individuals at high-risk (i.e., primary sclerosing cholangitis (PSC)). Here, we searched for protein biomarkers in serum extracellular vesicles (EVs). Methods: EVs from patients with isolated PSC (n=45), concomitant PSC-CCA (n=42), PSC who developed CCA during follow-up (PSC to CCA; n=25), CCAs from non-PSC etiology (n=56), hepatocellular carcinoma (n=34) and healthy individuals (n=55) were characterized by mass-spectrometry. Diagnostic biomarkers of PSC-CCA, non-PSC CCA or CCAs regardless etiology (pan-CCAs) were defined, and their expression was evaluated in human organs/tissues and within CCA tumors at single-cell level. Prognostic EV-biomarkers for CCA were investigated. Results: High-throughput proteomics identified candidate diagnostic biomarkers for PSC-CCA, non-PSC CCA or pan-CCA, as well as and for differential diagnosis of intrahepatic CCA and HCC, that were cross-validated by ELISA using total serum. Machine learning logit modelling disclosed CRP/FRIL/Fibrinogen algorithm with diagnostic value for early-stage PSC-CCA vs isolated PSC (AUC=0.944; OR=82.0), overpowering CA19-9 (AUC=0.735; OR=9.3). An algorithm combining CRP/VWF/PIGR/ /Fibrinogen allowed the diagnosis of early-stage non-PSC CCAs compared to healthy individuals (AUC=0.999; OR=1115). Noteworthy, levels of Fibrinogen/CRP/PIGR/FRIL showed predictive capacity for CCA development in patients with PSC before clinical evidences of malignancy. Multi-organ transcriptomic analysis revealed that serum EV-biomarkers were mostly expressed in hepatobiliary tissues, and scRNA-seq and immunofluorescence analysis of CCA tumors showed their presence mainly in malignant cholangiocytes. Multivariable analysis unveiled EVprognostic biomarkers independent to clinical features, with COMP/GNAI2/CFAI and ACTN1/MYCT1/PF4V associated negatively or positively to patients’ survival, respectively. Conclusions: Serum EVs contain protein biomarkers for the prediction, early diagnosis and prognosis estimation of CCA, representing a novel tumor cell-derived liquid biopsy for personalized medicine.