The Aplidin analogs PM01215 and PM02781 inhibit angiogenesis in vitro and in vivo. Issue 1 (December 2015)

• Record Type: Journal Article
• Authors: Borjan, Bojana; Steiner, Normann; Karbon, Silvia; Kern, Johann; Francesch, Andrés; Hermann, Martin; Willenbacher, Wolfgang; Gunsilius, Eberhard; Untergasser, Gerold
• Is Part Of: BMC cancer. Volume 15:Issue 1(2015)
• Page Start: 1
• Page End: 16
• Publication Date: 2015-12
• Subjects: Aplidin analogs -- Angiogenesis -- Oxidative stress -- UPR -- Vasohibin -- Dickkopf-3 -- p16INK4A; Cancer -- Periodicals; 616.994005
• DOI: 10.1186/s12885-015-1729-4
• Languages: English
• ISSNs: 1471-2407

Abstract

Abstract Background Novel synthesized analogs of Aplidin, PM01215 and PM02781, were tested for antiangiogenic effects on primary human endothelial cellsin vitro and for inhibition of angiogenesis and tumor growthin vivo . Methods Antiangiogenic activity of both derivatives was evaluated by real-time cell proliferation, capillary tube formation and vascular endothelial growth factor (VEGF)-induced spheroid sprouting assays. Distribution of endothelial cells in the different phases of the cell cycle was analyzed by flow cytometry. Aplidin analogs were testedin vivo in chicken chorioallantoic membrane (CAM) assays. Results Both derivatives inhibited angiogenic capacities of human endothelial cells (HUVECs)in vitro at low nanomolar concentrations. Antiangiogenic effects of both analogs were observed in the CAM. In addition, growth of human multiple myeloma xenograftsin vivo in CAM was significantly reduced after application of both analogs. On the molecular level, both derivatives induced cell cycle arrest in G1 phase. This growth arrest of endothelial cells correlated with induction of the cell cycle inhibitor p16INK4A and increased senescence-associated beta galactosidase activity. In addition, Aplidin analogs induced oxidative stress and decreased production of the vascular maturation factors Vasohibin-1 and Dickkopf-3. Conclusions From these findings we conclude that both analogs are promising agents for the development of antiangiogenic drugs acting independent on classical inhibition of VEGF signaling.