Phomaketide A inhibits lymphangiogenesis in human lymphatic endothelial cells
Journal
Marine Drugs
Journal Volume
17
Journal Issue
4
Date Issued
2019
Author(s)
Tai, Huai-Ching
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
Abstract
Lymphangiogenesis 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 C (PKC), 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, PKC, 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. ? 2019 by the authors.
Subjects
Lymphangiogenesis; Lymphatic endothelial cells; Phomaketide a; Vascular endothelial growth factor receptor-3
Other Subjects
antineoplastic agent; endothelial nitric oxide synthase; fungal extract; phomaketide A; protein kinase C delta; rapamycin; unclassified drug; vasculotropin receptor 3; angiogenesis inhibitor; antinematodal agent; endothelial nitric oxide synthase; FLT4 protein, human; NOS3 protein, human; polyketide; PRKCD protein, human; protein kinase C delta; vasculotropin receptor 3; animal experiment; animal model; animal tissue; antineoplastic activity; Article; cancer inhibition; controlled study; drug identification; drug isolation; drug mechanism; drug structure; endothelium cell; human; human cell; lung adenocarcinoma; lymph vessel endothelium; lymphangiogenesis; male; metastasis inhibition; migration inhibition; mouse; nonhuman; Phoma; tumor vascularization; A-549 cell line; animal; aquatic species; Ascomycetes; chemistry; cytology; drug effect; drug screening; endothelium cell; isolation and purification; lymph node metastasis; lymph vessel; lymphangiogenesis; metabolism; neoplasm; nude mouse; pathology; signal transduction; A549 Cells; Angiogenesis Inhibitors; Animals; Antinematodal Agents; Aquatic Organisms; Ascomycota; Endothelial Cells; Humans; Lymphangiogenesis; Lymphatic Metastasis; Lymphatic Vessels; Male; Mice; Mice, Nude; Neoplasms; Nitric Oxide Synthase Type III; Polyketides; Protein Kinase C-delta; Signal Transduction; Vascular Endothelial Growth Factor Receptor-3; Xenograft Model Antitumor Assays
Type
journal article