The marine fungal metabolite, AD0157, inhibits angiogenesis by targeting the Akt signaling pathway.
In the course of a screening program for the inhibitors of angiogenesis from marine sources, AD0157, a pyrrolidinedione fungal metabolite, was selected for its angiosupressive properties. AD0157 inhibited the growth of endothelial and tumor cells in culture in the micromolar range. Our results show that subtoxic doses of this compound inhibit certain functions of endothelial cells, namely, differentiation, migration and proteolytic capability. Inhibition of the mentioned essential steps of in vitro angiogenesis is in agreement with the observed antiangiogenic activity, substantiated by using two in vivo angiogenesis models, the chorioallantoic membrane and the zebrafish embryo neovascularization assays, and by the ex vivo mouse aortic ring assay. Our data indicate that AD0157 induces apoptosis in endothelial cells through chromatin condensation, DNA fragmentation, increases in the subG1 peak and caspase activation. The data shown here altogether indicate for the first time that AD0157 displays antiangiogenic effects, both in vitro and in vivo, that are exerted partly by targeting the Akt signaling pathway in activated endothelial cells. The fact that these effects are carried out at lower concentrations than those required for other inhibitors of angiogenesis makes AD0157 a new promising drug candidate for further evaluation in the treatment of cancer and other angiogenesis-related pathologies.
Department of Molecular Biology and Biochemistry, Faculty of Sciences, University of Málaga, Campus de Teatinos, Málaga 29071, Spain. melissa@uma.es.
Melissa
M
García-Caballero
Department of Molecular Biology and Biochemistry, Faculty of Sciences, University of Málaga, Campus de Teatinos, Málaga 29071, Spain. acanedohe@terra.es.
Librada
L
Cañedo
Department of Molecular Biology and Biochemistry, Faculty of Sciences, University of Málaga, Campus de Teatinos, Málaga 29071, Spain. a.fernandez@biomar.co.
Antonio
A
Fernández-Medarde
Department of Molecular Biology and Biochemistry, Faculty of Sciences, University of Málaga, Campus de Teatinos, Málaga 29071, Spain. medina@uma.es.
Miguel Ángel
MÁ
Medina
Department of Molecular Biology and Biochemistry, Faculty of Sciences, University of Málaga, Campus de Teatinos, Málaga 29071, Spain. quesada@uma.es.
Ana R
AR
Quesada
D020533:Angiogenesis Inhibitors; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002196:Capillaries / Q000502:physiology; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004625:Embryo, Nonmammalian / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005109:Extracellular Matrix / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D051058:Oncogene Protein v-akt / Q000187:drug effects* / Q000502:physiology; D010766:Phosphorylation; D011809:Quinones / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D013388:Succinimides / Q000494:pharmacology; D015027:Zebrafish / Q000502:physiology
C000590753:AD0157; D020533:Angiogenesis Inhibitors; D002843:Chromatin; D011809:Quinones; D013388:Succinimides; D051058:Oncogene Protein v-akt; D020169:Caspases