Ampelopsin Inhibits Cell Proliferation and Induces Apoptosis in HL60 and K562 Leukemia Cells by Downregulating AKT and NF-κB Signaling Pathways

Jang Mi Han,Hye Jin Jung,Hong Lae Kim

doi:10.3390/ijms22084265

Abstract

Leukemia is a type of blood cancer caused by the rapid proliferation of abnormal white blood cells. Currently, several treatment options, including chemotherapy, radiation therapy, and bone marrow transplantation, are used to treat leukemia, but the morbidity and mortality rates of patients with leukemia are still high. Therefore, there is still a need to develop more selective and less toxic drugs for the effective treatment of leukemia. Ampelopsin, also known as dihydromyricetin, is a plant-derived flavonoid that possesses multiple pharmacological functions, including antibacterial, anti-inflammatory, antioxidative, antiangiogenic, and anticancer activities. However, the anticancer effect and mechanism of action of ampelopsin in leukemia remain unclear. In this study, we evaluated the antileukemic effect of ampelopsin against acute promyelocytic HL60 and chronic myelogenous K562 leukemia cells. Ampelopsin significantly inhibited the proliferation of both leukemia cell lines at concentrations that did not affect normal cell viability. Ampelopsin induced cell cycle arrest at the sub-G1 phase in HL60 cells but the S phase in K562 cells. In addition, ampelopsin regulated the expression of cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors differently in each leukemia cell. Ampelopsin also induced apoptosis in both leukemia cell lines through nuclear condensation, loss of mitochondrial membrane potential, increase in reactive oxygen species (ROS) generation, activation of caspase-9, caspase-3, and poly ADP-ribose polymerase (PARP), and regulation of Bcl-2 family members. Furthermore, the antileukemic effect of ampelopsin was associated with the downregulation of AKT and NF-κB signaling pathways. Moreover, ampelopsin suppressed the expression levels of leukemia stemness markers, such as Oct4, Sox2, CD44, and CD133. Taken together, our findings suggest that ampelopsin may be an attractive chemotherapeutic agent against leukemia.

Highlights

HL60 Acute myeloid leukemia (AML) and K562 chronic myeloid leukemia (CML) cell lines were treated with ampelopsin (0–400 μM) for 24 or
The IC50 values of ampelopsin for HL60 and K562 cells were 60.77 and 156.2 μM at 24 h and 45.1 and 135.2 μM at 48 h, respectively, indicating that ampelopsin more potently inhibited the proliferation of HL60 cells than that of K562 cells
To further characterize the apoptosis induced by ampelopsin in leukemia cells, we investigated whether it causes nuclear apoptotic changes in HL60 and K562 cells

Summary

Introduction

AML is an aggressive malignancy characterized by abnormal proliferation of myeloid progenitor cells and is strongly associated with mutations in the FMS-like tyrosine kinase 3 (FLT3) gene or the abnormal fusion gene promyelocytic leukemia/retinoic acid receptor alpha (PML/RARA) [3,5]. Aberrantly activated FLT3 and BCR-ABL tyrosine kinases and PML/RARα fusion protein have emerged as promising molecular targets for the treatment of AML and CML. Several tyrosine kinase inhibitors (TKIs), such as FLT3 inhibitors (sorafenib and midostaurin) and BCR-ABL inhibitors (imatinib and nilotinib), and PML/RARα inhibitors (all-trans retinoic acid and arsenic trioxide) have been developed and clinically applied to patients with AML and CML as single agents or in combination with chemotherapy [7,8,9,10]. The most definitive and effective treatment for leukemia is bone marrow transplantation [11]

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Conclusion