Paeonol enhances the sensitivity of human ovarian cancer cells to radiotherapy-induced apoptosis due to downregulation of the phosphatidylinositol-3-kinase/Akt/phosphatase and tensin homolog pathway and inhibition of vascular endothelial growth factor

Abstract

Abstract. Radiotherapy is a vital and effective method to treat solid tumors. However, in many tumor types, development of resistance of cancer cells and cytotoxicity in normal tissues presents a major therapeutic problem. It is therefore crucial to identify and develop novel sensitizing agents that may improve the response to radiation therapy without causing any adverse effects. The present study aimed to investigate whether paeonol, a bioactive flavonoid, was able to confer sensitivity to radiation in human ovarian cancer cells. The human ovarian cancer cell lines SKOV-3 and OVCAR-3 were exposed to varying doses of radiation (2, 4 or 6 Gy) in the presence or absence of paeonol (25, 50 or 100 µM). Radiosensitivity was assessed by measuring cell viability using a CCK-8 assay and Annexin V/PI staining. Expression of vascular endothelial growth factor (VEGF), hypoxia inducible factor-1α (HIF-1α), proteins of the phosphatidylinositol-3-kinase (PI3K)/Akt pathway and apoptotic pathway proteins [caspase-3, Bcl-2-associated death promoter, B-cell lymphoma (Bcl)-2, Bcl-2-associated X and Bcl-extra large (Bcl-xL)] were also assessed. Paeonol treatment enhanced apoptosis of SKOV-3 and OVCAR-3 cells that were exposed to radiation. The expression of Bcl-2 and Bcl-xL were markedly upregulated in these cells. Treatment with paeonol concentrations of 50 and 100 µM caused a significant downregulation of VEGF, HIF-1α and PI3K/Akt pathway proteins. Paeonol effectively enhanced the sensitivity of ovarian cancer cells to radiation by significantly altering regulation of the proteins of the PI3K/Akt pathway, in addition to downregulating VEGF and HIF-1α.

Paeonol protects against testicular ischaemia‐reperfusion injury in rats through inhibition of oxidative stress and inflammation

“…In the current study, paeonol prevented the elevation of testicular expression of HIF‐1α in comparison with the IR group. Paeonol enhanced the sensitivity of ovarian cancer cells to radiation by downregulating HIF‐1α expression (Zhou, Sun, & Cheng, 2017). Consequently, paeonol, by its antioxidant and anti‐inflammatory effect, could prevent the activation of HIF‐1α in the testes of IR injured rats.…”

To Explore the Pathogenesis of Vascular Lesion of Type 2 Diabetes Mellitus Based on the PI3K/Akt Signaling Pathway

“…Vascular endothelial cells are highly differentiated monolayer cells which cover the surface of the vascular lumen and serve important functions including regulating vascular permeability, maintaining blood flow, and regulating vascular smooth muscle cell proliferation. Endothelial cell apoptosis may increase smooth muscle cell proliferation and migration, enhance blood coagulation, and increase leukocyte infiltration into the endothelium thus leading to endothelial dysfunction [17, 18]. Multiple metabolic disorders in type 2 diabetes mellitus accelerate this pathophysiological process.…”

Aberrant methylation of GADD45A is associated with decreased radiosensitivity in cervical cancer through the PI3K/AKT signaling pathway

“…The results demonstrated that the AKT inhibitor, MK-2206, enhanced the radiosensitivity of SiHa cells. It has been reported that the AKT signaling pathway promotes resistance to chemotherapy, radiotherapy and targeted therapy in different types of cancer, including colorectal cancer ( 41 ), non-small cell lung cancer ( 42 ), ovarian cancer ( 43 ) and glioma cell lines ( 44 ). Thus, it was hypothesized that downregulation of GADD45A decreases inactivation of the PI3K/AKT signaling pathway, and contributes to cellular resistance against radiotherapy.…”