Sesquiterpene Lactone Deoxyelephantopin Isolated from Elephantopus scaber and Its Derivative DETD-35 Suppress BRAF V600E Mutant Melanoma Lung Metastasis in Mice

• Published in: International journal of molecular sciences Vol. 22; no. 6
• Main Authors: Cvetanova, Biljana, Li, Meng-Yi, Yang, Chung-Chih, Hsiao, Pei-Wen, Yang, Yu-Chih, Feng, Jia-Hua, Shen, Ya-Ching, Nakagawa-Goto, Kyoko, Lee, Kuo-Hsiung, Shyur, Lie-Fen
• Format: Journal Article
• Language: English
• Published: Switzerland 22.03.2021
• Subjects: Animals; Antineoplastic Agents, Phytogenic - chemistry; Antineoplastic Agents, Phytogenic - isolation & purification; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis - drug effects; Apoptosis - genetics; Asteraceae - chemistry; Cell Cycle Checkpoints - drug effects; Cell Cycle Checkpoints - genetics; Cell Line, Tumor; Cell Proliferation - drug effects; Disease Models, Animal; Humans; Immunohistochemistry; Lactones - chemistry; Lactones - isolation & purification; Lactones - pharmacology; Lung Neoplasms - drug therapy; Lung Neoplasms - secondary; Melanoma - pathology; Mice; Mitochondria - drug effects; Mitochondria - metabolism; Molecular Structure; Oxidative Stress - drug effects; Plant Extracts - chemistry; Plant Extracts - isolation & purification; Plant Extracts - pharmacology; Proto-Oncogene Proteins B-raf - genetics; Reactive Oxygen Species - metabolism; Sesquiterpenes - chemistry; Sesquiterpenes - isolation & purification; Sesquiterpenes - pharmacology; Tumor Microenvironment - drug effects; Xenograft Model Antitumor Assays; mitochondria dysfunction; BRAFV600E metastatic melanoma; DETD-35; deoxyelephantopin; oxidative stress

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. DET and DETD-35 treatment inhibited A375LM5 cell proliferation, and induced G /M cell-cycle arrest and apoptosis. Furthermore, A375LM5 exhibited clonogenic, metastatic and invasive abilities, and several A375LM5 metastasis markers, -cadherin, MMP , 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 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 in NOD/SCID mice through inhibiting pulmonary vascular permeability and melanoma cell (Mel-A+) proliferation, angiogenesis (VEGF+, CD31+) and EMT ( -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 mutant melanoma.