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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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Detection of cytochrome c release in 10 µM aeroplysinin-1-treated BAE cells. Treatment of BAEC with staurosporine (STS) 2 µM was used as internal control of mitochondrial cytochrome c release. Representative blots from two different experiments are shown.
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marinedrugs-10-02033-f005: Detection of cytochrome c release in 10 µM aeroplysinin-1-treated BAE cells. Treatment of BAEC with staurosporine (STS) 2 µM was used as internal control of mitochondrial cytochrome c release. Representative blots from two different experiments are shown.

Mentions: Our data, suggesting a relevant role of caspase-9 activation in the aeroplysinin-1 apoptogenic activity, prompted us to investigate alterations in the physiology of the mitochondria caused by this drug. The intrinsic or mitochondrial apoptotic pathway is characterized by a permeabilization of the outer mitochondrial membrane induced by the pro-apoptotic stimuli, leading to the release of cytochrome c from the intermembrane space into the cytosol. Cytochrome c is a crucial component of the mitochondrial pathway of apoptosis, since by binding to the cytosolic apoptotic protease-activating factor 1 (Apaf-1), it contributes to the apoptosome assembly, which acts as an activation platform for procaspase-9 [14]. This feature was studied in digitonin-permeabilized BAE cells treated with 10 µM aeroplysinin-1 as described in Experimental Section. Treatment with aeroplysinin-1 elicited the redistribution of cytochrome c from mitochondria to cytosol, although the release seemed to be incomplete, as shown by the presence of cytochrome c in the pellet (Figure 5).


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)

Detection of cytochrome c release in 10 µM aeroplysinin-1-treated BAE cells. Treatment of BAEC with staurosporine (STS) 2 µM was used as internal control of mitochondrial cytochrome c release. Representative blots from two different experiments are shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

marinedrugs-10-02033-f005: Detection of cytochrome c release in 10 µM aeroplysinin-1-treated BAE cells. Treatment of BAEC with staurosporine (STS) 2 µM was used as internal control of mitochondrial cytochrome c release. Representative blots from two different experiments are shown.
Mentions: Our data, suggesting a relevant role of caspase-9 activation in the aeroplysinin-1 apoptogenic activity, prompted us to investigate alterations in the physiology of the mitochondria caused by this drug. The intrinsic or mitochondrial apoptotic pathway is characterized by a permeabilization of the outer mitochondrial membrane induced by the pro-apoptotic stimuli, leading to the release of cytochrome c from the intermembrane space into the cytosol. Cytochrome c is a crucial component of the mitochondrial pathway of apoptosis, since by binding to the cytosolic apoptotic protease-activating factor 1 (Apaf-1), it contributes to the apoptosome assembly, which acts as an activation platform for procaspase-9 [14]. This feature was studied in digitonin-permeabilized BAE cells treated with 10 µM aeroplysinin-1 as described in Experimental Section. Treatment with aeroplysinin-1 elicited the redistribution of cytochrome c from mitochondria to cytosol, although the release seemed to be incomplete, as shown by the presence of cytochrome c in the pellet (Figure 5).

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