Wogonin reverses multi-drug resistance of human myelogenous leukemia K562/A02 cells via downregulation of MRP1 expression by inhibiting Nrf2/ARE signaling pathway.

Abstract

Constitutive NF-E2-related factor 2 (Nrf2) activation has been recently reported to play a pivotal role in enhancing cell survival and resistance to anticancer drugs in many tumors. Previously, much effort has been devoted to the investigation of blocking Nrf2 function in cultured cells and cancer tissues, but few researches have been undertaken to evaluate the precise mechanism of flavonoids-induced sensitivity by inhibiting Nrf2. In this study, we investigated the reversal effect of Wogonin, a flavonoid isolated from the root of Scutellaria baicalensis Georgi, in resistant human myelogenous leukemia. Data indicated that Wogonin had strong reversal potency by inhibiting functional activity and expression of MRP1 at both protein and mRNA in adriamycin (ADR)-induced resistant human myelogenous leukemia K562/A02 cells. Consequently, the inhibition of MRP1 by Wogonin was dependent on Nrf2 through the decreased binding ability of Nrf2 to antioxidant response element (ARE). Further research revealed Wogonin modulated Nrf2 through the reduction of Nrf2mRNA at transcriptional processes rather than RNA degradation, which is regulated by the PI3K/Akt pathway. Moreover, DNA-PKcs was found to be involved in the Wogonin-induced downregulation of Nrf2 mRNA at transcriptional levels. In summary, these results clearly demonstrated the effectiveness of using Wogonin via inhibiting Nrf2 to combat chemoresistance and suggested that Wogonin can be developed into an efficient natural sensitizer for resistant human myelogenous leukemia.

• Authors: Xuefen Xu, Yi Zhang, Wei Li, Hanchi Miao, Haiwei Zhang, Yuxin Zhou, Zhiyu Li, Qidong You, Li Zhao, Qinglong Guo
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 92 Issue 2 Pg. 220-34 (Nov 15 2014) ISSN: 1873-2968 [Electronic] England
• PMID: 25264278 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Drugs, Chinese Herbal
• Flavanones
• Multidrug Resistance-Associated Proteins
• NF-E2-Related Factor 2
• NFE2L2 protein, human
• RNA, Messenger
• wogonin
• multidrug resistance-associated protein 1

Topics

• Antioxidant Response Elements (drug effects, physiology)
• Dose-Response Relationship, Drug
• Down-Regulation (drug effects, physiology)
• Drug Resistance, Multiple (drug effects, physiology)
• Drug Resistance, Neoplasm (drug effects, physiology)
• Drugs, Chinese Herbal (isolation & purification, pharmacology)
• Flavanones (isolation & purification, pharmacology)
• Gene Expression Regulation
• Humans
• K562 Cells
• Multidrug Resistance-Associated Proteins (antagonists & inhibitors, metabolism)
• NF-E2-Related Factor 2 (antagonists & inhibitors, biosynthesis)
• RNA, Messenger (antagonists & inhibitors, biosynthesis)
• Scutellaria baicalensis
• Signal Transduction (drug effects, physiology)