Phyto-sesquiterpene lactones DET and DETD-35 induce ferroptosis in vemurafenib sensitive and resistant melanoma via GPX4 inhibition and metabolic reprogramming. (April 2022)

• Record Type: Journal Article
• Authors: Chang, Meng-Ting; Tsai, Li-Chu; Nakagawa-Goto, Kyoko; Lee, Kuo-Hsiung; Shyur, Lie-Fen
• Is Part Of: Pharmacological research. Volume 178(2022)
• Publication Date: 2022-04
• Subjects: Deoxyelephantopin (PubChem CID: 6325056) -- DETD-35 -- Vemurafenib (PubChem CID: 42611257) -- (1S, 3R)-RSL3 (PubChem CID: 1750826) -- Ferrostatin-1 (PubChem CID: 4068248) -- ML162 (PubChem CID: 3689413); DET deoxyelephantopin -- GPX4 glutathione peroxidase 4 -- BRAFi BRAFV600E kinase inhibitor -- ROS reactive oxygen species -- FA fatty acid -- PUFA polyunsaturated fatty acid -- GSH glutathione -- LOX lipoxygenase -- cPLA2 cytosolic phospholipase A2; BRAF mutant melanoma -- Vemurafenib drug resistance -- Sesquiterpene lactone -- Metabolomics -- Ferroptosis -- GPX4 inhibitor; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2022.106148
• Languages: English
• ISSNs: 1043-6618

Abstract

Abstract: Acquired resistance to vemurafenib (PLX4032) is a thorny issue in BRAF V600E mutant melanoma therapy. Ferroptotic programmed cell death is a potential strategy for combating therapy-resistant cancers. This study uncovers the adaptation and abnormal upregulation of PUFAs and bioactive oxylipin metabolism in PLX4032 resistant melanoma cells. Phyto-sesquiterpene lactone, DET, and its derivative, DETD-35, induced lipid ROS accumulation and triggered ferroptotic cell death in PLX4032 sensitive (A375) and resistant (A375-R) BRAF V600E melanoma cells by reprogramming glutathione and primary metabolisms, lipid/oxylipin metabolism, and causing mitochondrial damage in which DETD-35 showed superior efficiency to DET. We discovered that DET and DETD-35 are a new type of GPX4 enzyme inhibitor through non-covalent binding. This study provides new insight into the therapeutic mechanisms of both DET and DETD-35 to combat PLX4032 sensitive/resistant BRAF V600E mutant melanomas via targeting GPX4 and ferroptosis. Graphical Abstract: ga1 Highlights: PLX4032 resistant melanoma shows upregulated PUFAs and derived bioactive oxylipins. DET and DETD-35 impair mitochondria and reprogram metabolic pathways in melanoma. DET and DETD-35 trigger ferroptosis via directly inhibiting GPX4 activity. Combining DET/DETD-35 and PLX4032 is promising for drug-resistant melanoma.