The potentiation of menadione on imatinib by downregulation of ABCB1 expression

Fei-Yan Xiao; Fang-Jiao Zhou; Fang Yuan; Wei Kuang; Gan Zhou; Hong-Hao Zhou; Shan Cao

doi:10.1111/1440-1681.13293

The potentiation of menadione on imatinib by downregulation of ABCB1 expression

Clin Exp Pharmacol Physiol. 2020 Jun;47(6):997-1004. doi: 10.1111/1440-1681.13293.

Authors

Fei-Yan Xiao^{1

2

3

4}, Fang-Jiao Zhou^{1

2

3

4}, Fang Yuan^{1

2

3

4}, Wei Kuang^{1

2

3

4}, Gan Zhou^{1

2

3

4

5}, Hong-Hao Zhou^{1

2

3

4}, Shan Cao^{1

2

3

4}

Affiliations

¹ Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.
² Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China.
³ Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China.
⁴ National Clinical Research Center for Geriatric Disorders, Changsha, China.
⁵ Institution of Drug Clinical Trial, Xiangya Hospital, Central South University, Changsha, China.

PMID: 32112424
DOI: 10.1111/1440-1681.13293

Abstract

Imatinib was the first BCR-ABL inhibitor used in clinical practice to treat chronic myeloid leukaemia (CML) and significantly improve the life expectancy of CML patients in the chronic phase. However, a portion of CML patients are resistant to imatinib. This study aimed to determine whether menadione (Vitamin K3) can improve imatinib efficacy in CML and to thoroughly explore the combination regimen mechanism between imatinib and menadione. Menadione improved imatinib efficacy in K562 cells by downregulating ABCB1 expression and increased the intracellular concentration of imatinib, which confirmed that this combination regimen is more effective than imatinib monotherapy. The results demonstrate that menadione and imatinib combination therapy may be a promising approach to refractory CML.

Keywords: ABCB1; chronic myeloid leukaemia; imatinib; menadione; potentiate.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ATP Binding Cassette Transporter, Subfamily B / genetics
ATP Binding Cassette Transporter, Subfamily B / metabolism
Antineoplastic Combined Chemotherapy Protocols / metabolism
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Cell Proliferation / drug effects
Down-Regulation
Drug Resistance, Neoplasm
Drug Synergism
Gene Expression Regulation, Neoplastic
Humans
Imatinib Mesylate / metabolism
Imatinib Mesylate / pharmacology*
K562 Cells
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
Protein Kinase Inhibitors / metabolism
Protein Kinase Inhibitors / pharmacology*
Vitamin K 3 / pharmacology*

Substances

ABCB1 protein, human
ATP Binding Cassette Transporter, Subfamily B
Protein Kinase Inhibitors
Vitamin K 3
Imatinib Mesylate