Reversal of doxorubicin resistance in lung cancer cells by neferine is explained by nuclear factor erythroid-derived 2-like 2 mediated lung resistance protein down regulation.

Content Provider	Europe PMC
Author	Paramasivan, Poornima Kumar, Jothi Dinesh Baskaran, Rathinasamy Weng, Ching Feng Padma, Viswanadha Vijaya
Abstract	Aim: Development of multi drug resistance and dose limiting cardiotoxicity are hindering the use of Doxorubicin (Dox) in clinical settings. Augmented dox efflux induced by lung resistance protein (LRP) over expression has been related to multi drug resistance phenotype in various cancers. An alkaloid from lotus, Neferine (Nef) shows both anticancer and cardioprotective effects. Here, we have investigated the interconnection between nuclear factor erythroid-derived 2-like 2 (NRF2) and LRP in Dox resistance and how Nef can overcome Dox resistance in lung cancer cells by altering this signaling.Methods: Anti-proliferative and apoptotic-inducing effects of Nef and Dox combination in Parental and Dox resistant lung cancer cells were determined in monolayers and 3D spheroids. Intracellular Dox was analyzed using flow cytometry, siRNA knockdown and western blot analysis were used to elucidate NRF2-LRP crosstalk mechanism.Results: We observed that the Dox resistant lung cancer cells expressed higher levels of LRP, reduced glutathione (GSH) and NRF2. Combination of Dox and Nef induced apoptosis, leads to reactive oxygen species (ROS) generation, GSH depletion and reduction in LRP levels contributing to higher intracellular and intranuclear Dox accumulation. The use of N-acetylcysteine and knockdown studies confirmed an important role of ROS and NRF2 in LRP down regulation. Presence of NRF2 binding sites in LRP is support of direct interaction between LRP and NRF2.Conclusion: Nef sensitizes lung cancer cells to Dox by increasing intracellular and/or intra nuclear Dox accumulation via LRP down regulation. This is mediated by redox regulating NRF2. This decoded crosstalk mechanism reinforces the role of NRF2 and LRP in Dox resistance and as an important anticancer target.
Related Links	https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC8992493&blobtype=pdf
Journal	Cancer Drug Resistance [Cancer Drug Resist]
Volume Number	3
DOI	10.20517/cdr.2019.115
PubMed Central reference number	PMC8992493
Issue Number	3
PubMed reference number	35582448
e-ISSN	2578532X
Language	English
Publisher	OAE Publishing Inc.
Publisher Date	2020-04-17
Access Restriction	Open
Rights License	© The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. © The Author(s) 2020.
Subject Keyword	Doxorubicin neferine reactive oxygen species lung resistance protein nuclear factor erythroid-derived 2-like 2 multidrug resistance
Content Type	Text
Resource Type	Article
Subject	Pharmacology (medical) Cancer Research