Issue 10, 2024

Disruption of lipid metabolism to induce ferroptosis using multifunctional fibrate-Pt(iv) prodrugs for cancer treatment

Abstract

Ferroptosis is an iron-mediated regulated cell death initiated by excessive membrane lipid peroxide accumulation. The intimate interplay between ferroptosis and lipid metabolism suggests that modulating lipid metabolism and activating ferroptosis may represent a broader cancer therapeutic space. Herein, two fibrate lipid-modulating agents, fenofibric acid and ciprofibrate, were employed to functionalize the clinical drug cisplatin through a Pt(IV) prodrug strategy, affording four fibrate-Pt(IV) anticancer prodrugs, compounds 1–4, with prominent anticancer activity and ferroptosis induction. The representative compounds, 1 and 3, exhibited antiproliferative activity up to 140- and 90-fold greater than cisplatin, respectively. Our data demonstrated that fibrate-Pt(IV) prodrugs accumulated in A549 cells much higher than cisplatin, followed by a dramatic decrease in intracellular lipid content, elevated reactive oxygen species (ROS) levels, disruption of the mitochondrial transmembrane potential, and remarkable proliferation inhibition. Moreover, our results revealed that fibrate-Pt(IV) prodrugs not only induced DNA damage, apoptosis, and cell cycle arrest, but also led to increases in lipid peroxides, ferrous ions, and malondialdehyde (MDA), as well as a decrease in glutathione, which triggers ferroptosis by suppressing the system Xc/GSH/GPX4 antioxidant defense axis and stimulation of the iron axis. Our results emphasize that combining lipid metabolism regulation with ferroptosis to develop new platinum-based anticancer agents can produce excellent multi-action anticancer activities, which may represent a promising cancer treatment modality.

Graphical abstract: Disruption of lipid metabolism to induce ferroptosis using multifunctional fibrate-Pt(iv) prodrugs for cancer treatment

Supplementary files

Article information

Article type
Research Article
Submitted
17 Feb 2024
Accepted
01 Apr 2024
First published
05 Apr 2024

Inorg. Chem. Front., 2024,11, 2914-2931

Disruption of lipid metabolism to induce ferroptosis using multifunctional fibrate-Pt(IV) prodrugs for cancer treatment

P. Sun, J. Wang, Q. Xie, X. Ren, X. Qiao and J. Xu, Inorg. Chem. Front., 2024, 11, 2914 DOI: 10.1039/D4QI00386A

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