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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., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Seven alkaloids (1-7) were isolated from the stem bark of Alangium longiflorum. Compound 1, (-)-10-O-demethylisocephaeline, was isolated for the first time as a naturally occurring product from a plant source. All structures were elucidated by detailed spectroscopic analysis. Biological evaluation showed that 2, 10-O-demethylcephaeline, exhibited potent cytotoxic activity against human lung carcinoma (A549) and breast adenocarcinoma (MCF-7) with ED(50) values of 0.013 and 0.062 microM, respectively. The stereoisomer 1 was less potent than 2, and related compounds with different hydroxy/methoxy substitution patterns were also less potent or inactive. Thus, compound 2 merits attention as a cytotoxic lead for further study.