PXD061935-1

PXD061935 is an original dataset announced via ProteomeXchange.

Title	Novel chemotherapy selectively induces double-strand DNA breaks and death in naïve and Cisplatin-resistant cholangiocarcinoma tumours - total proteomics and phosphoproteomics
Description	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.
HostingRepository	PRIDE
AnnounceDate	2025-11-10
AnnouncementXML	Submission_2025-11-09_19:57:05.458.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Mikel Azkargorta
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	phosphorylated residue
Instrument	timsTOF Pro

Revision	Datetime	Status	ChangeLog Entry
0	2025-03-17 12:24:09	ID requested
⏵ 1	2025-11-09 19:57:06	announced

10.1016/j.jhep.2025.04.034;

Olaizola I, Odriozola-Gimeno M, Olaizola P, Caballero-Camino FJ, Pastor-Toyos N, Tena-Garitaonaindia M, Lapitz A, Val B, Guimaraes AR, Asensio M, Huici-Izagirre M, Rae C, de Sancho D, Lopez X, Rodrigues PM, Herraez E, Briz O, Izquierdo-Sanchez L, Eleta-Lopez A, Bittner AM, Martinez-Amesti A, Miranda T, Ilyas SI, Braconi C, Perugorria MJ, Bujanda L, Rivilla I, Marin JJG, Coss, í, o FP, Banales JM, ve and cisplatin-resistant cholangiocarcinomas. J Hepatol, 83(5):1077-1091(2025) [pubmed]

submitter keyword: Cancer cells

Cancer-associated fibroblasts

Chemoresistance

Novel therapy

DNA crosslinks

Chromatin remodeling, phosphoproteomics, label free

Felix Elortza
contact affiliation	Proteomics Platform CIC bioGUNE Bizkaia Tech. Park Build. 800 Derio 48160 Spain
contact email	felortza@cicbiogune.es
lab head
Mikel Azkargorta
contact affiliation	Proteomics Platform CIC bioGUNE
contact email	mazkargorta@cicbiogune.es
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2025/11/PXD061935

PRIDE project URI

• PRIDE
  1. PXD061935
     1. Label: PRIDE project
     2. Name: Novel chemotherapy selectively induces double-strand DNA breaks and death in naïve and Cisplatin-resistant cholangiocarcinoma tumours - total proteomics and phosphoproteomics