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Original Article

Korean J Physiol Pharmacol 2022; 26(3): 145-155

Published online May 1, 2022 https://doi.org/10.4196/kjpp.2022.26.3.145

Copyright © Korean J Physiol Pharmacol.

Chemosensitizing effect and mechanism of imperatorin on the anti-tumor activity of doxorubicin in tumor cells and transplantation tumor model

Xin-li Liang1, Miao-miao Ji1, Zheng-gen Liao1, Guo-wei Zhao1, Xi-lan Tang2, and Wei Dong1,*

1Key Laboratory of Modern Preparation of Chinese Medicine, Ministry of Education, Jiangxi University of Chinese Medicine, Nanchang 330004, 2Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Nanchang 330013, China

Correspondence to:Wei Dong
E-mail: Paln7@163.com

Author contributions: X.L.L. contributed in collecting materials,design of the experiment and analysis of the data and drafted the paper. X.L.L. and M.M.J. contributed the experiment and instigation work, M.M.J. contributed to do the cell experiments and revising the manuscript, Z.G.L. contributed in the animal experiment and running the part of laboratory work. G.W.Z. and W.D. contributed to chromatographic analysis and critical reading of the manuscript. X.L.T. contributed to the design of the experiments and W.D. contributed to the edition of the manuscript. All the authors have read the final manuscript and approved the submission.

Received: December 4, 2020; Revised: November 7, 2021; Accepted: February 2, 2022

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Multidrug resistance of tumors has been a severe obstacle to the success of cancer chemotherapy. The study wants to investigate the reversal effects of imperatorin (IMP) on doxorubicin (DOX) resistance in K562/DOX leukemia cells, A2780/Taxol cells and in NOD/SCID mice, to explore the possible molecular mechanisms. K562/DOX and A2780/Taxol cells were treated with various concentrations of DOX and Taol with or without different concentrations of IMP, respectively. K562/DOX xenograft model was used to assess anti-tumor effect of IMP combined with DOX. MTT assay, Rhodamine 123 efflux assay, RT-PCR, and Western blot analysis were determined in vivo and in vitro. Results showed that IMP significantly enhanced the cytotoxicity of DOX and Taxol toward corresponding resistance cells. In vivo results illustrated both the tumor volume and tumor weight were significantly decreased after 2-week treatment with IMP combined with DOX compared to the DOX alone group. Western blotting and RT-PCR analyses indicated that IMP downregulated the expression of P-gp in K562/DOX xenograft tumors in NOD/SCID mice. We also evaluated glycolysis and glutamine metabolism in K562/DOX cells by measuring glucose consumption and lactate production. The results revealed that IMP could significantly reduce the glucose consumption and lactate production of K562/DOX cells. Furthermore, IMP could also remarkably repress the glutamine consumption, α-KG and ATP production of K562/DOX cells. Thus, IMP may sensitize K562/DOX cells to DOX and enhance the anti-tumor effect of DOX in K562/DOX xenograft tumors in NOD/SCID mice. IMP may be an adjuvant therapy to mitigate the multidrug resistance in leukemia chemotherapy.

Keywords: Doxorubicin, Imperatorin, Leukemia, Multidrug resistance, P-glycoprotein