Department of Biology, Faculty of Arts and Science, Uludag University, Bursa, Turkey.
Faculty of Veterinary Medicine, Department of Histology and Embryology, Istanbul University-Cerrahpasa, 34500 Buyukcekmece/Istanbul, Turkey.
Microvasc Res. 2021 Nov;138:104229. doi: 10.1016/j.mvr.2021.104229. Epub 2021 Jul 31.
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.
本研究评估了沙利度胺和钯（II）糖精酯与三联吡啶的配合物对抑制血管生成介导的细胞增殖的影响。用 ATP 法在 48 h 内单独用钯（II）配合物（1.56-100 μM）和沙利度胺（0.1-400 μM）处理后，评估其活力。结果发现，钯（II）配合物以剂量依赖性方式显著抑制 HUVECs 的生长，并通过产生 ROS 促进 PARP-1 裂解。另一方面，沙利度胺不会导致细胞活力发生任何显著变化。此外，用钯（II）配合物处理后观察到细胞死亡表现为晚期凋亡，因为在用 Annexin V/SYTOX 染色后 Annexin V/SYTOX 染色，而沙利度胺则没有表现出类似的结果。沙利度胺和钯（II）配合物也以时间依赖性方式抑制 HUVEC 的迁移和体外毛细血管样结构管形成。钯（II）配合物（5 mg/ml）处理显示出与阳性对照沙利度胺（5 mg/ml）相似的强烈抗血管生成作用，并成功破坏了血管，与对照（琼脂）相比，降低了血管的厚度。此外，自噬的抑制增强了沙利度胺和钯（II）配合物的细胞死亡和抗血管生成作用。我们还表明，用沙利度胺和钯（II）配合物处理会抑制 VEGFR2 下游信号调节剂的磷酸化。这些结果为通过抑制 FAK/Src/Akt/ERK1/2 信号通路来调节与血管生成相关的内皮细胞功能提供了证据。我们的结果还表明，PLC-γ1 磷酸化导致 p-Akt 和 p-Erk1/2 的激活，这导致在较低剂量下刺激细胞增殖。因此，我们证明钯（II）和沙利度胺可以通过 Erk/Akt/PLCγ 信号通路诱导细胞死亡，并且该通路可能是一种新的机制。
