Redox Biology (Dec 2023)
Organic Selenium induces ferroptosis in pancreatic cancer cells
- Roberta Noè,
- Noemi Inglese,
- Patrizia Romani,
- Thauan Serafini,
- Carlotta Paoli,
- Beatrice Calciolari,
- Marco Fantuz,
- Agata Zamborlin,
- Nicoletta C. Surdo,
- Vittoria Spada,
- Martina Spacci,
- Sara Volta,
- Maria Laura Ermini,
- Giulietta Di Benedetto,
- Valentina Frusca,
- Claudio Santi,
- Konstantinos Lefkimmiatis,
- Sirio Dupont,
- Valerio Voliani,
- Luca Sancineto,
- Alessandro Carrer
Affiliations
- Roberta Noè
- Veneto Institute of Molecular Medicine (VIMM), 35129, Padova, Italy; Department of Biology, University of Padova, 35126, Padova, Italy
- Noemi Inglese
- Veneto Institute of Molecular Medicine (VIMM), 35129, Padova, Italy; Department of Biology, University of Padova, 35126, Padova, Italy
- Patrizia Romani
- Department of Molecular Medicine, University of Padova, 35126, Padova, Italy
- Thauan Serafini
- Veneto Institute of Molecular Medicine (VIMM), 35129, Padova, Italy
- Carlotta Paoli
- Veneto Institute of Molecular Medicine (VIMM), 35129, Padova, Italy; Department of Biology, University of Padova, 35126, Padova, Italy
- Beatrice Calciolari
- Veneto Institute of Molecular Medicine (VIMM), 35129, Padova, Italy; Department of Biology, University of Padova, 35126, Padova, Italy
- Marco Fantuz
- Veneto Institute of Molecular Medicine (VIMM), 35129, Padova, Italy; Department of Biology, University of Padova, 35126, Padova, Italy
- Agata Zamborlin
- NEST-Scuola Normale Superiore, 56127, Pisa, Italy; Center for Nanotechnology Innovation, Istituto Italiano di Tecnologia, 56127, Pisa, Italy
- Nicoletta C. Surdo
- Veneto Institute of Molecular Medicine (VIMM), 35129, Padova, Italy; Neuroscience Institute, National Research Council (CNR), 35121, Padova, Italy
- Vittoria Spada
- Veneto Institute of Molecular Medicine (VIMM), 35129, Padova, Italy
- Martina Spacci
- Veneto Institute of Molecular Medicine (VIMM), 35129, Padova, Italy; Department of Biology, University of Padova, 35126, Padova, Italy
- Sara Volta
- Veneto Institute of Molecular Medicine (VIMM), 35129, Padova, Italy
- Maria Laura Ermini
- Center for Nanotechnology Innovation, Istituto Italiano di Tecnologia, 56127, Pisa, Italy
- Giulietta Di Benedetto
- Veneto Institute of Molecular Medicine (VIMM), 35129, Padova, Italy; Neuroscience Institute, National Research Council (CNR), 35121, Padova, Italy
- Valentina Frusca
- Center for Nanotechnology Innovation, Istituto Italiano di Tecnologia, 56127, Pisa, Italy; Scuola Superiore Sant’Anna, Piazza Martiri della Libertà 33, 56127, Pisa, Italy
- Claudio Santi
- Group of Catalysis and Green Organic Chemistry, Department of Pharmaceutical Sciences, University of Perugia, 06122, Perugia, PG, Italy
- Konstantinos Lefkimmiatis
- Veneto Institute of Molecular Medicine (VIMM), 35129, Padova, Italy; Department of Molecular Medicine, University of Pavia, Pavia, Italy
- Sirio Dupont
- Department of Molecular Medicine, University of Padova, 35126, Padova, Italy
- Valerio Voliani
- Center for Nanotechnology Innovation, Istituto Italiano di Tecnologia, 56127, Pisa, Italy; Department of Pharmacy, School of Medical and Pharmaceutical Sciences, University of Genova, 16148, Genoa, Italy; Corresponding author. Department of Pharmacy, School of Medical and Pharmaceutical Sciences, University of Genoa, 16148, Genoa, Italy.
- Luca Sancineto
- Group of Catalysis and Green Organic Chemistry, Department of Pharmaceutical Sciences, University of Perugia, 06122, Perugia, PG, Italy; Corresponding author. Department of Pharmaceutical Sciences, University of Perugia.
- Alessandro Carrer
- Veneto Institute of Molecular Medicine (VIMM), 35129, Padova, Italy; Department of Biology, University of Padova, 35126, Padova, Italy; Corresponding author. Veneto Institute of Molecular Medicine (VIMM), 35129, Padova, Italy.
- Journal volume & issue
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Vol. 68
p. 102962
Abstract
Pancreatic ductal adenocarcinoma (PDA) cells reprogram both mitochondrial and lysosomal functions to support growth. At the same time, this causes significant dishomeostasis of free radicals. While this is compensated by the upregulation of detoxification mechanisms, it also represents a potential vulnerability.Here we demonstrate that PDA cells are sensitive to the inhibition of the mevalonate pathway (MVP), which supports the biosynthesis of critical antioxidant intermediates and protect from ferroptosis. We attacked the susceptibility of PDA cells to ferroptotic death with selenorganic compounds, including dibenzyl diselenide (DBDS) that exhibits potent pro-oxidant properties and inhibits tumor growth in vitro and in vivo. DBDS treatment induces the mobilization of iron from mitochondria enabling uncontrolled lipid peroxidation. Finally, we showed that DBDS and statins act synergistically to promote ferroptosis and provide evidence that combined treatment is a viable strategy to combat PDA.
