Acquired resistance to vemurafenib (PLX4032) is a thorny issue in BRAF 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 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 mutant melanomas via targeting GPX4 and ferroptosis.
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Phytosesquiterpene lactones deregulate mitochondrial activity and phenotypes associated with triple-negative breast cancer metastasis.
Phytomedicine
December 2024
Molecular and Biological Agricultural Sciences Program, Taiwan International Graduate Program, Academia Sinica, Taipei 11529, Taiwan; Agricultural Biotechnology Research Center, Academia Sinica, Taipei 11529, Taiwan; Biotechnology Center, National Chung Hsing University, Taichung 40227, Taiwan; Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei 11031, Taiwan; PhD Program in Translational Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. Electronic address:
Background: Triple-negative breast cancer (TNBC) recurrence and metastasis are the major causes of failure in TNBC therapy. The difficulties in treating TNBCs may be because of increased cancer cell plasticity that involves the fine-tuning of cellular redox homeostasis, mitochondrial bioenergetics, metabolic characteristics, and the development of cancer stem cells (CSCs).
Purpose: To investigate the effects and the underlying mechanisms of the phytosesquiterpene lactone deoxyelephantopin (DET) and its semi-synthesized derivative (DETD-35) in suppressing different phenotypic TNBC cell populations that contribute to tumor metastasis.
MicroRNA-Mediated Mitochondrial Dysfunction Is Involved in the Anti-triple-Negative Breast Cancer Cell Activity of Phytosesquiterpene Lactones.
Antioxid Redox Signal
January 2023
Molecular and Biological Agricultural Sciences Program, Taiwan International Graduate Program, Academia Sinica and National Chung Hsing University, Taipei, Taiwan.
Emerging evidence suggests that modulating redox homeostasis through targeting mitochondrial functions may be a useful strategy for suppressing triple-negative breast cancer (TNBC) activities. However, whether there are specific microRNAs (miRNAs) involved in regulating oxidative stress-associated mitochondrial functions that can act as therapeutic targets to suppress TNBC activities remains unclear. Here, we aimed to identify the role of redox-associated miRNAs in TNBC and investigated their potential as therapeutic targets.
View Article and Find Full Text PDFPhyto-sesquiterpene lactones DET and DETD-35 induce ferroptosis in vemurafenib sensitive and resistant melanoma via GPX4 inhibition and metabolic reprogramming.
Pharmacol Res
April 2022
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:
Acquired resistance to vemurafenib (PLX4032) is a thorny issue in BRAF 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.
View Article and Find Full Text PDFSesquiterpene Lactone Deoxyelephantopin Isolated from and Its Derivative DETD-35 Suppress BRAF Mutant Melanoma Lung Metastasis in Mice.
Int J Mol Sci
March 2021
Agricultural Biotechnology Research Center, Academia Sinica, No. 128, Sec. 2, Academia Road, Nankang, Taipei 115, Taiwan.
Melanoma is a highly metastatic disease with an increasing rate of incidence worldwide. It is treatment refractory and has poor clinical prognosis; therefore, the development of new therapeutic agents for metastatic melanoma are urgently required. In this study, we created a lung-seeking A375LM5 BRAF mutant melanoma cell clone and investigated the bioefficacy of a plant sesquiterpene lactone deoxyelephantopin (DET) and its novel semi-synthetic derivative, DETD-35, in suppressing metastatic A375LM5 melanoma growth in vitro and in a xenograft mouse model.
View Article and Find Full Text PDFPhytoagent deoxyelephantopin derivative inhibits triple negative breast cancer cell activity by inducing oxidative stress-mediated paraptosis-like cell death.
Oncotarget
August 2017
Institute of Biotechnology, National Taiwan University, Taipei, Taiwan.
Triple negative breast cancer (TNBC) is a highly metastatic cancer among the breast cancer subgroups. A thorny issue for clinical therapy of TNBC is lack of an efficient targeted therapeutic strategy. We previously created a novel sesquiterpene lactone analog (named DETD-35) derived from plant deoxyelephantopin (DET) which exhibits potent effects against human TNBC MDA-MB-231 tumor growth in a xenograft mouse model.
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