Abstract
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 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 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.
Highlights
Melanoma, which develops from the malignant transformation of melanocytes, accounts for 2–4% of skin cancer incidence [1,2]
To explore the anti-metastatic potential of DET and DETD-35, our team established a V-raf murine sarcoma viral (BRAF)-mutant human melanoma lung-seeking clone that we named A375LM5IF4g/Luc
A375 BRAFV600E human melanoma cells with stable firefly luciferase reporter genes driven by a hybrid EF1α/eIF4g promoter were injected into the tail vein of NOD/SCID mice, and the lung metastases lesions were primarily cultured ex vivo to recover the metastatic A375LMIF4g/Luc cells
Summary
Melanoma, which develops from the malignant transformation of melanocytes, accounts for 2–4% of skin cancer incidence [1,2]. Even though the annual incidence of nonmelanoma skin cancers is far greater (over five million in United States alone), melanoma is the most fatal skin cancer and causes the vast majority (50–75%) of all cutaneous cancer deaths [2,3]. The estimated number of new cases of cutaneous melanoma in situ for 2020 was around 100,000, with 6850 estimated deaths from the metastatic disease in the United States alone [4]. II), where surgery is more curative, the five-year survival rate is 98.4%; in stage. For patients diagnosed with advanced melanoma (stage IV), the five-year survival rate is only 17.9% [5]
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