Dieckol is a natural brown algal-derived polyphenol and its cytotoxic potential against various types of cancer cells has been studied. However, the effects of dieckol on autophagy in cancer cells remain unknown. Here, we show that dieckol inhibits the growth of A375 human melanoma cells by inducing apoptotic cell death, which is associated with lysosomal dysfunction and the inhibition of autophagic flux. Dieckol induces autophagosome accumulation by inhibiting autophagosome-lysosome fusion. Moreover, dieckol not only triggers lysosomal membrane permeabilization, followed by an increase in lysosomal pH and the inactivation of cathepsin B and D, but also causes the loss of mitochondrial membrane potential. Importantly, a cathepsin D inhibitor partially relieved dieckol-induced mitochondrial membrane impairment and caspase-mediated apoptosis. Collectively, our findings indicate that dieckol is a novel autophagy inhibitor that induces apoptosis-mediated cell death via lysosomal dysfunction and mitochondrial membrane impairment in A375 human melanoma cells. This suggests the novel potential value of dieckol as a chemotherapeutic drug candidate for melanoma treatment.

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 Streptomyces-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.