Abstract
Aeroplysinin-1 is a brominated metabolite extracted from the marine sponge Aplysina aerophoba that has been previously characterized by our group as a potent antiangiogenic compound in vitro and in vivo. In this work, we provide evidence of a selective induction of apoptosis by aeroplysinin-1 in endothelial cells. Studies on the nuclear morphology of treated cells revealed that aeroplysinin-1 induces chromatin condensation and nuclear fragmentation, and it increases the percentage of cells with sub-diploid DNA content in endothelial, but not in HCT-116, human colon carcinoma and HT-1080 human fibrosarcoma cells. Treatment of endothelial cells with aeroplysinin-1 induces activation of caspases-2, -3, -8 and -9, as well as the cleavage of apoptotic substrates, such as poly (ADP-ribose) polymerase and lamin-A in a caspase-dependent mechanism. Our data indicate a relevant role of the mitochondria in the apoptogenic activity of this compound. The observation that aeroplysinin-1 prevents the phosphorylation of Bad relates to the mitochondria-mediated induction of apoptosis by this compound.
Highlights
Angiogenesis, the generation process of new capillaries from a pre-existing vascular bed, is a highly regulated mechanism of vascularization, which in adults is restricted to processes such as the female reproductive cycle and wound healing
We demonstrated that aeroplysinin-1 could induce apoptosis in endothelial cells, the mechanisms leading to apoptosis remained elusive (Figure 1B)
Our results suggest that the apoptosis-inducing mechanism of aeroplysinin-1 is endothelial cell-specific and dependent on the apoptogenic mitochondrial pathway through activation of the BH3-only pro-apoptotic protein Bad, cyrochrome c release and activation of caspases 2, 3, 8 and 9
Summary
Angiogenesis, the generation process of new capillaries from a pre-existing vascular bed, is a highly regulated mechanism of vascularization, which in adults is restricted to processes such as the female reproductive cycle and wound healing. Abnormal angiogenesis has been related to a number of pathological processes, such as tumor growth, metastasis, diabetic retinopathy, age-related macular degeneration, psoriasis and arthritis, among others [1]. For this reason, angiogenesis inhibition has attracted extensive attention in the field of pharmacological research, as well as becoming an emergent approach for the treatment of cancer and other angiogenesis-related diseases [2]. Our results suggest that the apoptosis-inducing mechanism of aeroplysinin-1 is endothelial cell-specific and dependent on the apoptogenic mitochondrial pathway through activation of the BH3-only pro-apoptotic protein Bad, cyrochrome c release and activation of caspases 2, 3, 8 and 9
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