Palladium (II) complex and thalidomide intercept angiogenic signaling via targeting FAK/Src and Erk/Akt/PLCγ dependent autophagy pathways in human umbilical vein endothelial cells

• Published in: Microvascular research 2021-11, Vol.138, p.104229-104229, Article 104229
• Main Authors: Aydinlik, Seyma, Uvez, Ayca, Kiyan, Hulya Tuba, Gurel-Gurevin, Ebru, Yilmaz, Veysel Turan, Ulukaya, Engin, Armutak, Elif Ilkay
• Format: Article
• Language: English
• Subjects: Angiogenesis; Angiogenesis Inhibitors - pharmacology; Animals; Apoptosis - drug effects; Autophagy; Autophagy - drug effects; Cells, Cultured; Chick chorioallantoic membrane (CAM); Chick Embryo; Coordination Complexes - pharmacology; Extracellular Signal-Regulated MAP Kinases - metabolism; Focal Adhesion Kinase 1 - metabolism; Human umbilical vein endothelial cells (HUVECs); Human Umbilical Vein Endothelial Cells - drug effects; Human Umbilical Vein Endothelial Cells - enzymology; Humans; Neovascularization, Physiologic - drug effects; Oxidative Stress - drug effects; Palladium complex; Phospholipase C gamma - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Reactive Nitrogen Species - metabolism; Signal Transduction; src-Family Kinases - metabolism; Thalidomide - pharmacology; VEGF pathway
• ISSN: 0026-2862; 1095-9319
• DOI: 10.1016/j.mvr.2021.104229

The current study assessed the effects of the thalidomide and palladium (II) saccharinate complex of terpyridine on the suppression of angiogenesis-mediated cell proliferation. The viability was assessed after treatment with palladium (II) complex (1.56–100 μM) and thalidomide (0.1–400 μM) alone by using ATP assay for 48 h. Palladium (II) complex was found to inhibit growth statistically significant in a dose-dependent manner in HUVECs and promoted PARP-1 cleavage through the production of ROS. On the other hand, thalidomide did not cause any significant change in cell viability. Moreover, cell death was observed to be manifested as late apoptosis due to Annexin V/SYTOX staining after palladium (II) complex treatment however, thalidomide did not demonstrate similar results. Thalidomide and palladium (II) complex also suppressed HUVEC migration and capillary-like structure tube formation in vitro in a time-dependent manner. Palladium (II) complex (5 mg/ml) treatment showed a strong antiangiogenic effect similar to positive control thalidomide (5 mg/ml) and successfully disrupted the vasculature and reduced the thickness of the vessels compared to control (agar). Furthermore, suppression of autophagy enhanced the cell death and anti-angiogenic effect of thalidomide and palladium (II) complex. We also showed that being treated with thalidomide and palladium (II) complex inhibited phosphorylation of the signaling regulators downstream of the VEGFR2. These results provide evidence for the regulation of endothelial cell functions that are relevant to angiogenesis through the suppression of the FAK/Src/Akt/ERK1/2 signaling pathway. Our results also indicate that PLC-γ1 phosphorylation leads to activation of p-Akt and p-Erk1/2 which cause stimulation on cell proliferation at lower doses. Hence, we demonstrated that palladium (II) and thalidomide can induce cell death via the Erk/Akt/PLCγ signaling pathway and that this pathway might be a novel mechanism. [Display omitted] •Palladium (II) complex exerted antiangiogenic effect by promoting apoptosis through ROS activation in HUVECs.•Blockade of autophagy by palladium (II) complex could enhance the sensitivity of HUVECs to angiogenesis.•Palladium (II) complex reduced angiogenic responses by blocking Erk/Akt/PLC-γ1/FAK signaling pathways.•Palladium (II) complex might be a novel angiogenesis inhibitör.