Quercetin Induces Apoptosis via Downregulation of Vascular Endothelial Growth Factor/Akt Signaling Pathway in Acute Myeloid Leukemia Cells.

Huan Shi,Xiao-Wei Huang,Guo-Dong Lu,Xing Zhang,Zi-Xuan Wang,Hui-Qi Dai,Jing Zhou,Zhong-Jie Li,Yao Chen,Xin-Yu Li,Ji Feng,Sayantan Chatterjee,Yong Wu,Jigang Wang,Hong-Qiao Wei,Pan-Hong Chen

doi:10.3389/fphar.2020.534171

Abstract

Acute myeloid leukemia (AML) is an aggressive haematological malignancy characterized by highly proliferative accumulation of immature and dysfunctional myeloid cells. Quercetin (Qu), one kind of flavonoid, exhibits anti-cancer property in multiple types of solid tumor, but its effect on acute myeloid leukemia is less studied, and the underlying mechanisms still largely unknown. This study aimed to explore the specific target and potential mechanism of quercetin-induced cell death in AML. First, we found that quercetin induces cell death in the form of apoptosis, which was caspase dependent. Second, we found that quercetin-induced apoptosis depends on the decrease of mitochondria membrane potential (MMP) and Bcl-2 proteins. With quantitative chemical proteomics, we observed the downregulation of VEGFR2 and PI3K/Akt signaling in quercetin-treated cells. Consistently, cell studies also identified that VEGFR2 and PI3K/Akt signaling pathways are involved in the action of quercetin on mitochondria and Bcl-2 proteins. The decrease of MMP and cell death could be rescued when PI3K/Akt signaling is activated, suggesting that VEGFR2 and PI3K/Akt exert as upstream regulators for quercetin effect on apoptosis induction in AML cells. In conclusion, our findings from this study provide convincing evidence that quercetin induces cell death via downregulation of VEGF/Akt signaling pathways and mitochondria-mediated apoptosis in AML cells.

Highlights

Acute myeloid leukemia (AML) is the most common acute leukemia in adults
We detected the release of lactate dehydrogenase (LDH), and our result indicated that quercetin treatment induced LDH release in a dose-dependent manner in both AML cell lines (Figure 1B)
Hoechst staining results suggested that quercetin is able to induce apoptotic cell death in AML cells. These results collectively indicated that quercetin promotes apoptotic cell death in AML cells

Summary

Introduction

Acute myeloid leukemia (AML) is the most common acute leukemia in adults This disease is an aggressive hematological malignancy characterized by highly proliferative accumulation of immature and dysfunctional myeloid cells (Saultz and Garzon, 2016). Some growth factor pathways have been reported to show significant impacts on the development of AML, especially vascular endothelial growth factor (VEGF) could offer leukemia cells advantages on proliferation, survival, and chemotherapy resistance via both autocrine and paracrine manners (Dias et al, 2001; Papaemmanuil et al, 2016). Current studies demonstrated that exogenous VEGF can protect AML cells from chemotherapyinduced apoptosis (Jayson et al, 2016), and agents against VEGF/ VEGFR pathway, including anti-VEGF antibody and small molecular tyrosine kinase inhibitors, have been introduced in leukemia therapy (Madlambayan et al, 2010)

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