Phomaketide A Inhibits Lymphangiogenesis in Human Lymphatic Endothelial Cells
AbstractLymphangiogenesis is an important biological process associated with cancer metastasis. The development of new drugs that block lymphangiogenesis represents a promising therapeutic strategy. Marine fungus-derived compound phomaketide A, isolated from the fermented broth of Phoma sp. NTOU4195, has been reported to exhibit anti-angiogenic and anti-inflammatory effects. However, its anti-lymphangiogenic activity has not been clarified to date. In this study, we showed that phomaketide A inhibited cell growth, migration, and tube formation of lymphatic endothelial cells (LECs) without an evidence of cytotoxicity. Mechanistic investigations revealed that phomaketide A reduced LECs-induced lymphangiogenesis via vascular endothelial growth factor receptor-3 (VEGFR-3), protein kinase Cδ (PKCδ), and endothelial nitric oxide synthase (eNOS) signalings. Furthermore, human proteome array analysis indicated that phomaketide A significantly enhanced the protein levels of various protease inhibitors, including cystatin A, serpin B6, tissue factor pathway inhibitor (TFPI), and tissue inhibitor matrix metalloproteinase 1 (TIMP-1). Importantly, phomaketide A impeded tumor growth and lymphangiogenesis by decreasing the expression of LYVE-1, a specific marker for lymphatic vessels, in tumor xenograft animal model. These results suggest that phomaketide A may impair lymphangiogenesis by suppressing VEGFR-3, PKCδ, and eNOS signaling cascades, while simultaneously activating protease inhibitors in human LECs. We document for the first time that phomaketide A inhibits lymphangiogenesis both in vitro and in vivo, which suggests that this natural product could potentially treat cancer metastasis. View Full-Text
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Tai, H.-C.; Lee, T.-H.; Tang, C.-H.; Chen, L.-P.; Chen, W.-C.; Lee, M.-S.; Chen, P.-C.; Lin, C.-Y.; Chi, C.-W.; Chen, Y.-J.; Lai, C.-T.; Chen, S.-S.; Liao, K.-W.; Lee, C.-H.; Wang, S.-W. Phomaketide A Inhibits Lymphangiogenesis in Human Lymphatic Endothelial Cells. Mar. Drugs 2019, 17, 215.
Tai H-C, Lee T-H, Tang C-H, Chen L-P, Chen W-C, Lee M-S, Chen P-C, Lin C-Y, Chi C-W, Chen Y-J, Lai C-T, Chen S-S, Liao K-W, Lee C-H, Wang S-W. Phomaketide A Inhibits Lymphangiogenesis in Human Lymphatic Endothelial Cells. Marine Drugs. 2019; 17(4):215.Chicago/Turabian Style
Tai, Huai-Ching; Lee, Tzong-Huei; Tang, Chih-Hsin; Chen, Lei-Po; Chen, Wei-Cheng; Lee, Ming-Shian; Chen, Pei-Chi; Lin, Chih-Yang; Chi, Chih-Wen; Chen, Yu-Jen; Lai, Cheng-Ta; Chen, Shiou-Sheng; Liao, Kuang-Wen; Lee, Chien-Hsing; Wang, Shih-Wei. 2019. "Phomaketide A Inhibits Lymphangiogenesis in Human Lymphatic Endothelial Cells." Mar. Drugs 17, no. 4: 215.
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