A novel mitochondria-targeting DHODH inhibitor induces robust ferroptosis and alleviates immune suppression.
Pharmacol Res
; 202: 107115, 2024 Apr.
Article
em En
| MEDLINE
| ID: mdl-38423231
ABSTRACT
Dihydroorotate dehydrogenase (DHODH)-mediated ferroptosis defense is a targetable vulnerability in cancer. Currently, only a few DHODH inhibitors have been utilized in clinical practice. To further enhance DHODH targeting, we introduced the mitochondrial targeting group triphenylphosphine (TPP) to brequinar (BRQ), a robust DHODH inhibitor, resulting in the creation of active molecule B2. This compound exhibits heightened anticancer activity, effectively inhibiting proliferation in various cancer cells, and restraining tumor growth in melanoma xenografts in mice. B2 achieves these effects by targeting DHODH, triggering the formation of reactive oxygen species (ROS), promoting mitochondrial lipid peroxidation, and inducing ferroptosis in B16F10 and A375 cells. Surprisingly, B2 significantly downregulates PD-L1 and alleviates immune suppression. Importantly, B2 exhibits no apparent adverse effects in mice. Collectively, these findings highlight that enhancing the mitochondrial targeting capability of the DHODH inhibitor is a promising therapeutic approach for melanoma treatment.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Oxirredutases atuantes sobre Doadores de Grupo CH-CH
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Ferroptose
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Melanoma
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article