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

Meng-Ting Chang; Li-Chu Tsai; Kyoko Nakagawa-Goto; Kuo-Hsiung Lee; Lie-Fen Shyur

doi:10.1016/j.phrs.2022.106148

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

Pharmacol Res. 2022 Apr:178:106148. doi: 10.1016/j.phrs.2022.106148. Epub 2022 Feb 26.

Authors

Meng-Ting Chang¹, Li-Chu Tsai², Kyoko Nakagawa-Goto³, Kuo-Hsiung Lee⁴, Lie-Fen Shyur⁵

Affiliations

¹ Department of Biochemical Science and Technology, National Taiwan University, Taipei 110, Taiwan; Agricultural Biotechnology Research Center, Academia Sinica, Taipei 115, Taiwan.
² Department of Molecular Science and Engineering, National Taipei University of Technology, Taipei 106, Taiwan.
³ College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
⁴ Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
⁵ Department of Biochemical Science and Technology, National Taiwan University, Taipei 110, Taiwan; Agricultural Biotechnology Research Center, Academia Sinica, Taipei 115, Taiwan; Ph.D. Program in Translational Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. Electronic address: [email protected].

PMID: 35231572
DOI: 10.1016/j.phrs.2022.106148

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.

Keywords: (1S,3R)-RSL3 (PubChem CID: 1750826); BRAF mutant melanoma; DETD-35; Deoxyelephantopin (PubChem CID: 6325056); Ferroptosis; Ferrostatin-1 (PubChem CID: 4068248); GPX4 inhibitor; ML162 (PubChem CID: 3689413); Metabolomics; Sesquiterpene lactone; Vemurafenib (PubChem CID: 42611257); Vemurafenib drug resistance.

MeSH terms

Cell Line, Tumor
Drug Resistance, Neoplasm
Enzyme Inhibitors / pharmacology
Ferroptosis* / drug effects
Humans
Indoles / pharmacology
Lactones / pharmacology
Melanoma* / drug therapy
Melanoma* / genetics
Melanoma* / metabolism
Oxylipins / metabolism
Phospholipid Hydroperoxide Glutathione Peroxidase* / antagonists & inhibitors
Proto-Oncogene Proteins B-raf / metabolism
Sesquiterpenes* / pharmacology
Sulfonamides / pharmacology
Vemurafenib / pharmacology

Substances

Enzyme Inhibitors
Indoles
Lactones
Oxylipins
Sesquiterpenes
Sulfonamides
Vemurafenib
Phospholipid Hydroperoxide Glutathione Peroxidase
Proto-Oncogene Proteins B-raf