Abstract
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.
Highlights
Angiogenesis, a physiological process involving the generation of new capillaries from pre-existing vessels, is strictly controlled by a balance of stimulators and inhibitors, being restricted in adults to some processes related to the reproductive cycle and wound repair
Our results indicate the potential of AD0157 for the treatment of cancer and other angiogenesis-related malignancies and reinforce the concept that marine compounds are a valuable source of new inhibitors of angiogenesis
The data obtained with the HT-1080 fibrosarcoma cell line, HT-29 colon adenocarcinoma cell line, MDA-MB-231 breast carcinoma cell line and U2OS osteosarcoma cell line are in the same range of concentrations as that of bovine aortic endothelial cells (BAECs), suggesting that AD0157 is not a specific inhibitor of endothelial cell growth
Summary
Angiogenesis, a physiological process involving the generation of new capillaries from pre-existing vessels, is strictly controlled by a balance of stimulators and inhibitors, being restricted in adults to some processes related to the reproductive cycle and wound repair. A continuously increasing number of other non-neoplastic diseases are being related to an upregulated angiogenesis. They include diabetic retinopathy, age-related macular degeneration, hemangioma, arthritis and psoriasis, among others [2]. Activated endothelial cells will proliferate and avoid apoptosis, which could be triggered by the loss of survival signals and, will differentiate, rendering a new capillary. Any of these steps could be a target for the pharmacological inhibition of angiogenesis [5]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
