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The antiangiogenic compound aeroplysinin-1 induces apoptosis in endothelial cells by activating the mitochondrial pathway.

Martínez-Poveda B, Rodríguez-Nieto S, García-Caballero M, Medina MÁ, Quesada AR - Mar Drugs (2012)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology and Biochemistry, Faculty of Sciences, University of Málaga, Málaga E-29071, Spain. bmpoveda@gmail.com

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.

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Multiple molecular targets (indicated with a star) are involved in the pro-apoptotic effect of aeroplysinin-1 observed in endothelial cells. Bad is dephosphorylated and it translocates from cytosol to mitochondria, where it dimerizes with Bcl-XL and promotes the release of cytochrome c, activating caspase-9 (C9) and other downstream caspases.
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marinedrugs-10-02033-f007: Multiple molecular targets (indicated with a star) are involved in the pro-apoptotic effect of aeroplysinin-1 observed in endothelial cells. Bad is dephosphorylated and it translocates from cytosol to mitochondria, where it dimerizes with Bcl-XL and promotes the release of cytochrome c, activating caspase-9 (C9) and other downstream caspases.

Mentions: Little is known about aeroplysinin-1 and how it can selectively target endothelial cells. Several reports provide evidence concerning the inhibitory effect of aeroplysinin-1 on EGF receptor in vitro and in vivo [26,27], although this effect has been questioned by others [28]. No data is available about the inhibitory capacity of aeroplysinin-1 on key steps of the signal transduction pathways controlling angiogenesis. Taken together, our results led us to suggest a mechanism by which aeroplysinin-1, through inhibition of Bad phosphorylation, could orchestrate the decision to undergo endothelial apoptosis by mitochondria permeabilization, cytochrome c release and further activation of the caspases proteolytic cascade (Figure 7). Undoubtedly, more experimental efforts will be required to elucidate this issue.


The antiangiogenic compound aeroplysinin-1 induces apoptosis in endothelial cells by activating the mitochondrial pathway.

Martínez-Poveda B, Rodríguez-Nieto S, García-Caballero M, Medina MÁ, Quesada AR - Mar Drugs (2012)

Multiple molecular targets (indicated with a star) are involved in the pro-apoptotic effect of aeroplysinin-1 observed in endothelial cells. Bad is dephosphorylated and it translocates from cytosol to mitochondria, where it dimerizes with Bcl-XL and promotes the release of cytochrome c, activating caspase-9 (C9) and other downstream caspases.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3475271&req=5

marinedrugs-10-02033-f007: Multiple molecular targets (indicated with a star) are involved in the pro-apoptotic effect of aeroplysinin-1 observed in endothelial cells. Bad is dephosphorylated and it translocates from cytosol to mitochondria, where it dimerizes with Bcl-XL and promotes the release of cytochrome c, activating caspase-9 (C9) and other downstream caspases.
Mentions: Little is known about aeroplysinin-1 and how it can selectively target endothelial cells. Several reports provide evidence concerning the inhibitory effect of aeroplysinin-1 on EGF receptor in vitro and in vivo [26,27], although this effect has been questioned by others [28]. No data is available about the inhibitory capacity of aeroplysinin-1 on key steps of the signal transduction pathways controlling angiogenesis. Taken together, our results led us to suggest a mechanism by which aeroplysinin-1, through inhibition of Bad phosphorylation, could orchestrate the decision to undergo endothelial apoptosis by mitochondria permeabilization, cytochrome c release and further activation of the caspases proteolytic cascade (Figure 7). Undoubtedly, more experimental efforts will be required to elucidate this issue.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology and Biochemistry, Faculty of Sciences, University of Málaga, Málaga E-29071, Spain. bmpoveda@gmail.com

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.

Show MeSH
Related in: MedlinePlus