Targeting SKP2/Bcr-Abl pathway with Diosmetin suppresses chronic myeloid leukemia proliferation

Yuan Liu; Zhenlong Shao; Yuning Liao; Xiaohong Xia; Chuyi Huang; Jinchan He; Tumei Hu; Cuifu Yu; Lili Jiang; Jinbao Liu; Hongbiao Huang

doi:10.1016/j.ejphar.2020.173366

Targeting SKP2/Bcr-Abl pathway with Diosmetin suppresses chronic myeloid leukemia proliferation

Eur J Pharmacol. 2020 Sep 15:883:173366. doi: 10.1016/j.ejphar.2020.173366. Epub 2020 Jul 15.

Authors

Affiliations

¹ Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, 510095, China; Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China.
² Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, 510095, China; Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China. Electronic address: jliu@gzhmu.edu.cn.
³ Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, 510095, China; Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China. Electronic address: hhb800616@126.com.

PMID: 32679184
DOI: 10.1016/j.ejphar.2020.173366

Abstract

Bcr-Abl is the primary cause as well as currently key therapeutic target of chronic myeloid leukemia (CML). SKP2, an E3 ligase, is a downstream factor of Bcr-Abl to motivate the cell cycle transition of CML and also found to bind and activate Bcr-Abl in reverse. Therefore, SKP2/Bcr-Abl pathway is an attractive target for CML treatment. This study aims to identify an inhibitor of the SKP2/Bcr-Abl pathway based on a large screening of the natural products. We demonstrate that Diosmetin, a kind of phytoestrogens, notably downregulates the expression of SKP2, Bcr-Abl phosphorylation, and moderately downregulates the Bcr-Abl level. Furthermore, Diosmetin displays a favorable anti-tumor activity in CML cells and xenograft models. Collectively, our study reveals a natural compound in the treatment of CML on the basis of SKP2/Bcr-Abl signaling pathway.

Keywords: Apoptosis; Bcr-Abl; CML; Diosmetin; SKP2.

MeSH terms

Animals
Antineoplastic Agents, Phytogenic / pharmacology*
Apoptosis / drug effects
Cell Proliferation / drug effects*
Down-Regulation
Drug Resistance, Neoplasm
Flavonoids / pharmacology*
Fusion Proteins, bcr-abl / metabolism*
Gene Expression Regulation, Neoplastic
Humans
Imatinib Mesylate / pharmacology
K562 Cells
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / enzymology
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
Male
Mice, Inbred BALB C
Mice, Nude
Phosphorylation
Protein Kinase Inhibitors / pharmacology*
S-Phase Kinase-Associated Proteins / antagonists & inhibitors*
S-Phase Kinase-Associated Proteins / genetics
S-Phase Kinase-Associated Proteins / metabolism
Signal Transduction
Tumor Burden / drug effects
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents, Phytogenic
BCR-ABL1 fusion protein, human
Flavonoids
Protein Kinase Inhibitors
S-Phase Kinase-Associated Proteins
SKP2 protein, human
Imatinib Mesylate
Fusion Proteins, bcr-abl
diosmetin