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

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2021Author
Aydinlik, SeymaUvez, Ayca
Kiyan, Hulya Tuba
Gurel-Gurevin, Ebru
Yilmaz, Veysel Turan
Ulukaya, Engin
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Aydinlik, S., Uvez, A., Kiyan, H. T., Gurel-Gurevin, E., Yilmaz, V. T., Ulukaya, E., & Armutak, E. I. (2021). 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. Microvascular research, 104229. Advance online publication. https://doi.org/10.1016/j.mvr.2021.104229Abstract
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 48h. 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 (5mg/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 antiangiogenic 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.