1,4-dihydroxy quininib activates ferroptosis pathways in metastatic uveal melanoma and reveals a novel prognostic biomarker signature

Valentina Tonelotto ^1,2, Marcel Costa-Garcia ³, Eve O'Reilly ^1,2

¹UCD Conway Institute, University College Dublin, D04 V1W8, Dublin, Ireland.
²UCD School of Biomolecular and Biomedical Science, University College Dublin, D04 V1W8, Dublin, Ireland.
³Medical Oncology Department, Catalan Institute of Cancer (ICO), IDIBELL-OncoBell, Barcelona, Spain.
⁴Mass Spectrometry Resource, Conway Institute of Biomolecular & Biomedical Research, University College Dublin, D04 V1W8, Dublin, Ireland.
⁵UCD School of Mathematics & Statistics, University College Dublin, D04 V1W8, Dublin, Ireland.
⁶Department of Life Sciences, University of Trieste, 34127, Trieste, Italy.
⁷Xenopat S.L., Business Bioincubator, Bellvitge Health Science Campus, 08907 L'Hospitalet de Llobregat, Barcelona, Spain.
⁸Program Against Cancer Therapeutic Resistance (ProCURE), ICO, IDIBELL, Barcelona, Spain.
⁹Department of Drug and Health Sciences, University of Catania, 95125, Catania, Italy.
¹⁰CERNUT-Research Centre on Nutraceuticals and Health Products, University of Catania, 95125, Catania, Italy.
¹¹UCD Conway Institute, University College Dublin, D04 V1W8, Dublin, Ireland. brendan.kennedy@ucd.ie.
¹²UCD School of Biomolecular and Biomedical Science, University College Dublin, D04 V1W8, Dublin, Ireland. brendan.kennedy@ucd.ie.

⁰UCD Conway Institute, University College Dublin, D04 V1W8, Dublin, Ireland.

Cell Death Discovery +

|

February 10, 2024

View abstract on PubMed

Summary

1,4-dihydroxy quininib targets ferroptosis, a cell death pathway, in metastatic uveal melanoma (MUM). This drug modulates key ferroptosis markers, offering potential as a biomarker and therapeutic target for this aggressive eye cancer.

Area Of Science

Oncology
Molecular Biology
Biochemistry

Background

Uveal melanoma (UM) is an aggressive eye cancer with a high propensity for lethal liver metastases (MUM).
Current treatments for MUM are limited, with poor patient survival rates.
1,4-dihydroxy quininib, a cysteinyl leukotriene receptor 1 (CysLT1) antagonist, shows promise in altering UM hallmarks.

Purpose Of The Study

To investigate the mechanism of action of 1,4-dihydroxy quininib in MUM.
To evaluate the translational potential of 1,4-dihydroxy quininib in MUM.
To identify novel ferroptosis signatures as prognosticators for MUM.

Main Methods

Proteomic profiling of OMM2.5 UM cells treated with 1,4-dihydroxy quininib.
Assessment of ferroptosis markers (GPX4, GCLM, HO-1, 4-HNE) via immunoblotting and biochemical assays.
Analysis of ferroptosis gene expression in UM patient data and correlation with survival.

Main Results

1,4-dihydroxy quininib significantly modulated ferroptosis markers in UM cells.
GPX4, biliverdin, GCLM, glutathione, and lipid hydroperoxide levels were altered by the drug.
Increased HO-1 and 4-HNE levels were observed in MUM tumor explants.
A novel ferroptosis signature (IFerr) was identified, correlating with UM patient survival.

Conclusions

1,4-dihydroxy quininib induces ferroptosis in MUM cells and tissues by modulating key markers.
The IFerr signature shows potential as a prognosticator for MUM development.
Ferroptosis represents a promising clinical biomarker and therapeutic target for MUM.