{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T06:30:58Z","timestamp":1779345058522,"version":"3.51.4"},"reference-count":53,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2021,3,22]],"date-time":"2021-03-22T00:00:00Z","timestamp":1616371200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Science and Technology, Taiwan and Academia Sinica, Taiwan","award":["MOST 106-2320-B-001-004-MY3, MOST 109-2320-B-001 -019 -MY3, AS-SUMMIT-108"],"award-info":[{"award-number":["MOST 106-2320-B-001-004-MY3, MOST 109-2320-B-001 -019 -MY3, AS-SUMMIT-108"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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 A375LM5IF4g\/Luc BRAFV600E 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 A375LM5IF4g\/Luc melanoma growth in vitro and in a xenograft mouse model. DET and DETD-35 treatment inhibited A375LM5IF4g\/Luc cell proliferation, and induced G2\/M cell-cycle arrest and apoptosis. Furthermore, A375LM5IF4g\/Luc exhibited clonogenic, metastatic and invasive abilities, and several A375LM5IF4g\/Luc metastasis markers, N-cadherin, MMP2, vimentin and integrin \u03b14 were significantly suppressed by treatment with either compound. Interestingly, DET- and DETD-35-induced Reactive Oxygen Species (ROS) generation and glutathione (GSH) depletion were found to be upstream events important for the in vitro activities, because exogenous GSH supplementation blunted DET and DETD-35 effects on A375LM5IF4g\/Luc cells. DET and DETD-35 also induced mitochondrial DNA mutation, superoxide production, mitochondrial bioenergetics dysfunction, and mitochondrial protein deregulation. Most importantly, DET and DETD-35 inhibited lung metastasis of A375LM5IF4g\/Luc in NOD\/SCID mice through inhibiting pulmonary vascular permeability and melanoma cell (Mel-A+) proliferation, angiogenesis (VEGF+, CD31+) and EMT (N-cadherin) in the tumor microenvironment in the lungs. These findings indicate that DET and DETD-35 may be useful in the intervention of lung metastatic BRAFV600E mutant melanoma.<\/jats:p>","DOI":"10.3390\/ijms22063226","type":"journal-article","created":{"date-parts":[[2021,3,22]],"date-time":"2021-03-22T11:13:26Z","timestamp":1616411606000},"page":"3226","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Sesquiterpene Lactone Deoxyelephantopin Isolated from Elephantopus scaber and Its Derivative DETD-35 Suppress BRAFV600E Mutant Melanoma Lung Metastasis in Mice"],"prefix":"10.3390","volume":"22","author":[{"given":"Biljana","family":"Cvetanova","sequence":"first","affiliation":[{"name":"School of Pharmacy, College of Medicine, National Taiwan University, Taipei 100, Taiwan"},{"name":"Agricultural Biotechnology Research Center, Academia Sinica, No. 128, Sec. 2, Academia Road, Nankang, Taipei 115, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meng-Yi","family":"Li","sequence":"additional","affiliation":[{"name":"Agricultural Biotechnology Research Center, Academia Sinica, No. 128, Sec. 2, Academia Road, Nankang, Taipei 115, Taiwan"},{"name":"Department of Biochemical Science and Technology, College of Life Science, National Taiwan University, Taipei 106, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chung-Chih","family":"Yang","sequence":"additional","affiliation":[{"name":"Agricultural Biotechnology Research Center, Academia Sinica, No. 128, Sec. 2, Academia Road, Nankang, Taipei 115, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pei-Wen","family":"Hsiao","sequence":"additional","affiliation":[{"name":"Agricultural Biotechnology Research Center, Academia Sinica, No. 128, Sec. 2, Academia Road, Nankang, Taipei 115, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu-Chih","family":"Yang","sequence":"additional","affiliation":[{"name":"Agricultural Biotechnology Research Center, Academia Sinica, No. 128, Sec. 2, Academia Road, Nankang, Taipei 115, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jia-Hua","family":"Feng","sequence":"additional","affiliation":[{"name":"Agricultural Biotechnology Research Center, Academia Sinica, No. 128, Sec. 2, Academia Road, Nankang, Taipei 115, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ya-Ching","family":"Shen","sequence":"additional","affiliation":[{"name":"School of Pharmacy, College of Medicine, National Taiwan University, Taipei 100, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1642-6538","authenticated-orcid":false,"given":"Kyoko","family":"Nakagawa-Goto","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan"},{"name":"Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7568, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6562-0070","authenticated-orcid":false,"given":"Kuo-Hsiung","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7568, USA"},{"name":"Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung 401, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lie-Fen","family":"Shyur","sequence":"additional","affiliation":[{"name":"Agricultural Biotechnology Research Center, Academia Sinica, No. 128, Sec. 2, Academia Road, Nankang, Taipei 115, Taiwan"},{"name":"Department of Biochemical Science and Technology, College of Life Science, National Taiwan University, Taipei 106, Taiwan"},{"name":"Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei 110, Taiwan"},{"name":"Institute of BioPharmaceutical Sciences, National Sun Yat-sen University, Kaohsiung 804, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1038\/nrc.2016.37","article-title":"From melanocytes to melanomas","volume":"16","author":"Shain","year":"2016","journal-title":"Nat. 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