Sesquiterpene Lactone Deoxyelephantopin Isolated from Elephantopus scaber and its Derivative DETD-35 Suppress BRAFV600E 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, 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 clonogenic, metastatic and invasive abilities and several A375LM5IF4g/Luc metastasis markers, N-cadherin, MMP2, vimentin and integrin 4 were significantly suppressed by treatment with either compound. Interestingly, DET- and DETD-35-induced ROS generation and GSH depletion were found to be upstream events important for the in vitro activities as 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.
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 and Lie-Fen Shyur*
(2021) Sesquiterpene Lactone Deoxyelephantopin Isolated from Elephantopus scaber and its Derivative DETD-35 Suppress BRAFV600E Mutant Melanoma Lung Metastasis in Mice
International Journal of Molecular Sciences, 2021, 22(6), 3226