Choi Byeoung-Kyu, Jo Min-Hee, Shin Hee Jae, Park Sun Joo
Department of Bio-Convergence Engineering, Dongyang Mirae University, Seoul 08221, Republic of Korea.
BB21 Plus Program, Department of Chemistry, Pukyong National University, Busan 48513, Republic of Korea.
Molecules. 2025 Feb 20;30(5):987. doi: 10.3390/molecules30050987.
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 -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.
血管生成主要由血管内皮生长因子（VEGF）及其受体VEGFR驱动，在癌症进展等各种病理过程中起关键作用。在此，我们研究了海洋来源化合物Lucknolide A（LA）的抗血管生成作用，并评估了其作为VEGFR2抑制剂的潜力。LA选择性抑制人内皮细胞EA.hy926和HUVEC的增殖，而对正常成纤维细胞和各种肿瘤细胞的影响极小。LA诱导EA.hy926细胞S期细胞周期停滞和凋亡，增加凋亡标志物p53、Bax和p21，降低抗凋亡蛋白Bcl-2，在VEGF刺激下这些作用进一步增强。此外，LA抑制VEGFR2磷酸化及其下游信号通路，包括对内皮细胞存活和血管生成至关重要的Akt/mTOR/p70S6K、MEK/ERK、Src、FAK和p38 MAPK。分子对接研究表明，LA与无活性（DFG-out，PDB：4ASD）和活性（DFG-in，PDB：3B8R）的VEGFR2构象均结合，对活性状态（-107.96 kcal/mol）的亲和力明显强于无活性状态（-33.56 kcal/mol），表明其具有作为VEGFR2激酶抑制剂的潜力。在功能上，LA在体外和离体大鼠主动脉环试验中均显著抑制VEGF诱导的内皮细胞迁移、管腔形成和微血管芽生。此外，LA减少了人乳腺肿瘤细胞（MDA-MB-231）诱导的肿瘤相关管腔形成，表明其具有抑制VEGF依赖性肿瘤血管生成的潜力。这些发现表明，LA是一种有前景的选择性抗血管生成剂，在癌症等血管生成相关疾病中具有潜在的治疗应用价值。
