Anti-Angiogenic Potential of Marine <i>Streptomyces</i>-Derived Lucknolide A on VEGF/VEGFR2 Signaling in Human Endothelial Cells
Angiogenesis, primarily driven by the vascular endothelial growth factor (VEGF) and its receptor, the VEGFR, plays a key role in various pathological processes such as cancer progression. Here, we investigated the anti-angiogenic effects of Lucknolide A (LA), a marine <i>Streptomyces</i>...
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2025-02-01
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| author | Byeoung-Kyu Choi Min-Hee Jo Hee Jae Shin Sun Joo Park |
| author_facet | Byeoung-Kyu Choi Min-Hee Jo Hee Jae Shin Sun Joo Park |
| author_sort | Byeoung-Kyu Choi |
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| description | Angiogenesis, primarily driven by the vascular endothelial growth factor (VEGF) and its receptor, the VEGFR, plays a key role in various pathological processes such as cancer progression. Here, we investigated the anti-angiogenic effects of Lucknolide A (LA), a marine <i>Streptomyces</i>-derived compound, and evaluated its potential as a VEGFR2 inhibitor. LA selectively inhibited the proliferation of human endothelial cells EA.hy926 and HUVEC while exhibiting minimal effects on normal fibroblasts and various tumor cells. LA induced S-phase cell cycle arrest and apoptosis in EA.hy926 cells, increasing apoptotic markers p53, Bax, and p21 and decreasing the anti-apoptotic protein Bcl-2, with these effects being further enhanced under VEGF stimulation. Additionally, LA suppressed VEGFR2 phosphorylation and its downstream signaling pathways, including Akt/mTOR/p70S6K, MEK/ERK, Src, FAK, and p38 MAPK, which are crucial for endothelial survival and angiogenesis. Molecular docking studies revealed that LA binds to both inactive (DFG-out, PDB: 4ASD) and active (DFG-in, PDB: 3B8R) VEGFR2 conformations, with a significantly stronger affinity for the active state (−107.96 kcal/mol) than the inactive state (−33.56 kcal/mol), suggesting its potential as a VEGFR2 kinase inhibitor. Functionally, LA significantly inhibited VEGF-induced endothelial migration, tube formation, and microvessel sprouting in both in vitro and ex vivo rat aortic ring assays. Additionally, LA reduced tumor-associated tube formation induced by human breast tumor cells (MDA-MB-231), indicating its potential to suppress VEGF-dependent tumor angiogenesis. These findings suggest that LA is a promising selective anti-angiogenic agent with potential therapeutic applications in angiogenesis-related diseases such as cancer. |
| format | Article |
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| publishDate | 2025-02-01 |
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| spelling | doaj-art-73c85907ff8e4e0691908ba64a1c90cb2025-08-20T02:05:24ZengMDPI AGMolecules1420-30492025-02-0130598710.3390/molecules30050987Anti-Angiogenic Potential of Marine <i>Streptomyces</i>-Derived Lucknolide A on VEGF/VEGFR2 Signaling in Human Endothelial CellsByeoung-Kyu Choi0Min-Hee Jo1Hee Jae Shin2Sun Joo Park3Department of Bio-Convergence Engineering, Dongyang Mirae University, Seoul 08221, Republic of KoreaBB21 Plus Program, Department of Chemistry, Pukyong National University, Busan 48513, Republic of KoreaMarine Natural Products Laboratory, Korea Institute of Ocean Science and Technology, Busan 49111, Republic of KoreaBB21 Plus Program, Department of Chemistry, Pukyong National University, Busan 48513, Republic of KoreaAngiogenesis, primarily driven by the vascular endothelial growth factor (VEGF) and its receptor, the VEGFR, plays a key role in various pathological processes such as cancer progression. Here, we investigated the anti-angiogenic effects of Lucknolide A (LA), a marine <i>Streptomyces</i>-derived compound, and evaluated its potential as a VEGFR2 inhibitor. LA selectively inhibited the proliferation of human endothelial cells EA.hy926 and HUVEC while exhibiting minimal effects on normal fibroblasts and various tumor cells. LA induced S-phase cell cycle arrest and apoptosis in EA.hy926 cells, increasing apoptotic markers p53, Bax, and p21 and decreasing the anti-apoptotic protein Bcl-2, with these effects being further enhanced under VEGF stimulation. Additionally, LA suppressed VEGFR2 phosphorylation and its downstream signaling pathways, including Akt/mTOR/p70S6K, MEK/ERK, Src, FAK, and p38 MAPK, which are crucial for endothelial survival and angiogenesis. Molecular docking studies revealed that LA binds to both inactive (DFG-out, PDB: 4ASD) and active (DFG-in, PDB: 3B8R) VEGFR2 conformations, with a significantly stronger affinity for the active state (−107.96 kcal/mol) than the inactive state (−33.56 kcal/mol), suggesting its potential as a VEGFR2 kinase inhibitor. Functionally, LA significantly inhibited VEGF-induced endothelial migration, tube formation, and microvessel sprouting in both in vitro and ex vivo rat aortic ring assays. Additionally, LA reduced tumor-associated tube formation induced by human breast tumor cells (MDA-MB-231), indicating its potential to suppress VEGF-dependent tumor angiogenesis. These findings suggest that LA is a promising selective anti-angiogenic agent with potential therapeutic applications in angiogenesis-related diseases such as cancer.https://www.mdpi.com/1420-3049/30/5/987Lucknolide Amarine natural compoundmarine <i>Streptomyces</i>anti-angiogenesisVEGF/VEGFR2 signalinganti-tumor |
| spellingShingle | Byeoung-Kyu Choi Min-Hee Jo Hee Jae Shin Sun Joo Park Anti-Angiogenic Potential of Marine <i>Streptomyces</i>-Derived Lucknolide A on VEGF/VEGFR2 Signaling in Human Endothelial Cells Molecules Lucknolide A marine natural compound marine <i>Streptomyces</i> anti-angiogenesis VEGF/VEGFR2 signaling anti-tumor |
| title | Anti-Angiogenic Potential of Marine <i>Streptomyces</i>-Derived Lucknolide A on VEGF/VEGFR2 Signaling in Human Endothelial Cells |
| title_full | Anti-Angiogenic Potential of Marine <i>Streptomyces</i>-Derived Lucknolide A on VEGF/VEGFR2 Signaling in Human Endothelial Cells |
| title_fullStr | Anti-Angiogenic Potential of Marine <i>Streptomyces</i>-Derived Lucknolide A on VEGF/VEGFR2 Signaling in Human Endothelial Cells |
| title_full_unstemmed | Anti-Angiogenic Potential of Marine <i>Streptomyces</i>-Derived Lucknolide A on VEGF/VEGFR2 Signaling in Human Endothelial Cells |
| title_short | Anti-Angiogenic Potential of Marine <i>Streptomyces</i>-Derived Lucknolide A on VEGF/VEGFR2 Signaling in Human Endothelial Cells |
| title_sort | anti angiogenic potential of marine i streptomyces i derived lucknolide a on vegf vegfr2 signaling in human endothelial cells |
| topic | Lucknolide A marine natural compound marine <i>Streptomyces</i> anti-angiogenesis VEGF/VEGFR2 signaling anti-tumor |
| url | https://www.mdpi.com/1420-3049/30/5/987 |
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