Sesquiterpene Lactone Deoxyelephantopin Isolated from <i>Elephantopus scaber</i> and Its Derivative DETD-35 Suppress BRAF<sup>V600E</sup> Mutant Melanoma Lung Metastasis in Mice
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<...
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MDPI AG
2021-03-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/6/3226 |
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| author | Biljana Cvetanova Meng-Yi Li Chung-Chih Yang Pei-Wen Hsiao Yu-Chih Yang Jia-Hua Feng Ya-Ching Shen Kyoko Nakagawa-Goto Kuo-Hsiung Lee Lie-Fen Shyur |
| author_facet | Biljana Cvetanova Meng-Yi Li Chung-Chih Yang Pei-Wen Hsiao Yu-Chih Yang Jia-Hua Feng Ya-Ching Shen Kyoko Nakagawa-Goto Kuo-Hsiung Lee Lie-Fen Shyur |
| author_sort | Biljana Cvetanova |
| collection | DOAJ |
| description | 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<i><sup>IF4g/Luc</sup></i> BRAF<i><sup>V600E</sup></i> 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<i><sup>IF4g/Luc</sup></i> melanoma growth in vitro and in a xenograft mouse model. DET and DETD-35 treatment inhibited A375LM5<i><sup>IF4g/Luc</sup></i> cell proliferation, and induced G<sub>2</sub>/M cell-cycle arrest and apoptosis. Furthermore, A375LM5<i><sup>IF4g/Luc</sup></i> exhibited clonogenic, metastatic and invasive abilities, and several A375LM5<i><sup>IF4g/Luc</sup></i> metastasis markers, <i>N</i>-cadherin, MMP<sub>2</sub>, vimentin and integrin α4 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 A375LM5<i><sup>IF4g/Luc</sup></i> 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 A375LM5<i><sup>IF4g/Luc</sup></i> in NOD/SCID mice through inhibiting pulmonary vascular permeability and melanoma cell (Mel-A+) proliferation, angiogenesis (VEGF+, CD31+) and EMT (<i>N</i>-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 BRAF<sup>V600E</sup> mutant melanoma. |
| first_indexed | 2024-03-10T13:01:19Z |
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| language | English |
| last_indexed | 2024-03-10T13:01:19Z |
| publishDate | 2021-03-01 |
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| spelling | doaj.art-c624358825684a9492e133d2332c5d2f2023-11-21T11:31:48ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-03-01226322610.3390/ijms22063226Sesquiterpene Lactone Deoxyelephantopin Isolated from <i>Elephantopus scaber</i> and Its Derivative DETD-35 Suppress BRAF<sup>V600E</sup> Mutant Melanoma Lung Metastasis in MiceBiljana Cvetanova0Meng-Yi Li1Chung-Chih Yang2Pei-Wen Hsiao3Yu-Chih Yang4Jia-Hua Feng5Ya-Ching Shen6Kyoko Nakagawa-Goto7Kuo-Hsiung Lee8Lie-Fen Shyur9School of Pharmacy, College of Medicine, National Taiwan University, Taipei 100, TaiwanAgricultural Biotechnology Research Center, Academia Sinica, No. 128, Sec. 2, Academia Road, Nankang, Taipei 115, TaiwanAgricultural Biotechnology Research Center, Academia Sinica, No. 128, Sec. 2, Academia Road, Nankang, Taipei 115, TaiwanAgricultural Biotechnology Research Center, Academia Sinica, No. 128, Sec. 2, Academia Road, Nankang, Taipei 115, TaiwanAgricultural Biotechnology Research Center, Academia Sinica, No. 128, Sec. 2, Academia Road, Nankang, Taipei 115, TaiwanAgricultural Biotechnology Research Center, Academia Sinica, No. 128, Sec. 2, Academia Road, Nankang, Taipei 115, TaiwanSchool of Pharmacy, College of Medicine, National Taiwan University, Taipei 100, TaiwanSchool of Pharmaceutical Sciences, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, JapanDivision of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7568, USAAgricultural Biotechnology Research Center, Academia Sinica, No. 128, Sec. 2, Academia Road, Nankang, Taipei 115, TaiwanMelanoma 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<i><sup>IF4g/Luc</sup></i> BRAF<i><sup>V600E</sup></i> 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<i><sup>IF4g/Luc</sup></i> melanoma growth in vitro and in a xenograft mouse model. DET and DETD-35 treatment inhibited A375LM5<i><sup>IF4g/Luc</sup></i> cell proliferation, and induced G<sub>2</sub>/M cell-cycle arrest and apoptosis. Furthermore, A375LM5<i><sup>IF4g/Luc</sup></i> exhibited clonogenic, metastatic and invasive abilities, and several A375LM5<i><sup>IF4g/Luc</sup></i> metastasis markers, <i>N</i>-cadherin, MMP<sub>2</sub>, vimentin and integrin α4 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 A375LM5<i><sup>IF4g/Luc</sup></i> 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 A375LM5<i><sup>IF4g/Luc</sup></i> in NOD/SCID mice through inhibiting pulmonary vascular permeability and melanoma cell (Mel-A+) proliferation, angiogenesis (VEGF+, CD31+) and EMT (<i>N</i>-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 BRAF<sup>V600E</sup> mutant melanoma.https://www.mdpi.com/1422-0067/22/6/3226BRAF<sup>V600E</sup> metastatic melanomadeoxyelephantopinDETD-35oxidative stressmitochondria dysfunction |
| spellingShingle | Biljana Cvetanova Meng-Yi Li Chung-Chih Yang Pei-Wen Hsiao Yu-Chih Yang Jia-Hua Feng Ya-Ching Shen Kyoko Nakagawa-Goto Kuo-Hsiung Lee Lie-Fen Shyur Sesquiterpene Lactone Deoxyelephantopin Isolated from <i>Elephantopus scaber</i> and Its Derivative DETD-35 Suppress BRAF<sup>V600E</sup> Mutant Melanoma Lung Metastasis in Mice International Journal of Molecular Sciences BRAF<sup>V600E</sup> metastatic melanoma deoxyelephantopin DETD-35 oxidative stress mitochondria dysfunction |
| title | Sesquiterpene Lactone Deoxyelephantopin Isolated from <i>Elephantopus scaber</i> and Its Derivative DETD-35 Suppress BRAF<sup>V600E</sup> Mutant Melanoma Lung Metastasis in Mice |
| title_full | Sesquiterpene Lactone Deoxyelephantopin Isolated from <i>Elephantopus scaber</i> and Its Derivative DETD-35 Suppress BRAF<sup>V600E</sup> Mutant Melanoma Lung Metastasis in Mice |
| title_fullStr | Sesquiterpene Lactone Deoxyelephantopin Isolated from <i>Elephantopus scaber</i> and Its Derivative DETD-35 Suppress BRAF<sup>V600E</sup> Mutant Melanoma Lung Metastasis in Mice |
| title_full_unstemmed | Sesquiterpene Lactone Deoxyelephantopin Isolated from <i>Elephantopus scaber</i> and Its Derivative DETD-35 Suppress BRAF<sup>V600E</sup> Mutant Melanoma Lung Metastasis in Mice |
| title_short | Sesquiterpene Lactone Deoxyelephantopin Isolated from <i>Elephantopus scaber</i> and Its Derivative DETD-35 Suppress BRAF<sup>V600E</sup> Mutant Melanoma Lung Metastasis in Mice |
| title_sort | sesquiterpene lactone deoxyelephantopin isolated from i elephantopus scaber i and its derivative detd 35 suppress braf sup v600e sup mutant melanoma lung metastasis in mice |
| topic | BRAF<sup>V600E</sup> metastatic melanoma deoxyelephantopin DETD-35 oxidative stress mitochondria dysfunction |
| url | https://www.mdpi.com/1422-0067/22/6/3226 |
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