NRF2 Modulators of Plant Origin and Their Ability to Overcome Multidrug Resistance in Cancers - Review

Sep 21, 2026

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Cancer remains a leading cause of death worldwide, and chemotherapy often fails due to multidrug resistance (MDR) acquired by cancer cells. MDR development is linked to the NRF2 transcription factor, which controls antioxidant and drug-resistance proteins including HO-1, NQO1, MRP1, MRP2, and GST. In normal cells, NRF2 protects against oxidative stress, but cancer cells may hyperactivate NRF2, enabling MDR and reducing chemotherapy efficacy. This review compiles current knowledge on plant-derived NRF2 inhibitors and summarizes their potential to counteract MDR.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages22

Reading Time55 min

AccessFree to download

Abstract

Keywords

1. Introduction

Multidrug resistance (MDR) and its acquisition strategies

NRF2/KEAP1 pathway and redox adaptation

Review NRF2 Modulators of Plant Origin and Their Ability to Overcome Multidrug Resistance in Cancers Piotr Wadowski 1,2, Michał Juszczak 1 and Katarzyna Wo´zniak 1, * Citation: Wadowski, P.; Juszczak, M.; Wo´zniak, K. NRF2 Modulators of Plant Origin and Their Ability to Overcome Multidrug Resistance in Cancers. Int. J. Mol. Sci. 2024, 25, 11500. [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)ijms252111500 Academic Editors: Simona Serini and Gabriella Calviello Received: 6 September 2024 Revised: 20 October 2024 Accepted: 23 October 2024 Published: 26 October 2024 Copyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) . 1 Department of Molecular Genetics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland; [piotr.wadowski@edu.uni.lodz.pl](piotr.wadowski@edu.uni.lodz.pl) (P.W.); [michal.juszczak@biol.uni.lodz.pl](michal.juszczak@biol.uni.lodz.pl) (M.J.) 2 Doctoral School of Exact and Natural Sciences, University of Lodz, Banacha 12/16, 90-237 Lodz, Poland * Correspondence: [katarzyna.wozniak@biol.uni.lodz.pl](katarzyna.wozniak@biol.uni.lodz.pl) Abstract: Cancer is one of the most common causes of death in the world. Despite the fact that there are many types of therapies available, cancer treatment remains a major challenge. The main reason for the ineffectiveness of chemotherapy is the acquisition of multidrug resistance (MDR) by cancer cells. One of the factors responsible for the acquisition of MDR is the NRF2 transcription factor, which regulates the expression of proteins such as HO-1, NQO1, MRP1, MRP2, and GST. In normal cells, NRF2 is the first line of defense against oxidative stress, thereby preventing carcinogenesis. Still, its hyperactivation in cancer cells causes them to acquire MDR, which significantly reduces or eliminates the effectiveness of chemotherapy. Considering the important role NRF2 plays in the acquisition of MDR, its modulators and, above all, inhibitors are being sought after, including among compounds of plant origin. NRF2 inhibition may prove to be a key element of anticancer therapy. This review summarizes the current state of knowledge about plant NRF2 inhibitors and presents the effects of their use in overcoming MDR in cancer. Keywords: NRF2 activators; NRF2 inhibitors; multidrug resistance; cancer; polyphenols; alkaloids 1. Introduction Multiple strategies for combating cancers have been developed throughout the years; despite this, there were 9.7 million deaths from cancer in the year 2022 worldwide. Moreover, there were close to 20 million new cases of cancer in that year [1] . One of the major factors leading to such a high mortality rate in cancers is the development of multidrug resistance (MDR), which makes the already difficult task of combating cancers even more complex. The most detrimental characteristic of MDR is that it leads to resistance to anticancer agents that are functionally and structurally different to those initially used in therapy. Cancer cells may acquire MDR through various strategies, such as elevated drug efflux, reduced drug intake, changes in drug targets and drug inactivation, epigenetic modifications, modulation of reactive oxygen species (ROS) levels and miRNA activity, improved DNA damage repair, inhibition of cell death, and detoxifying mechanisms, as well as the involvement of cancer stem cells, tumor heterogeneity, its microenvironment or mesenchymal transition (Figure 1) [2,3] . MDR cancer cells are characterized by their elevated antioxidant and scavenging enzyme levels, even when compared to other nonMDR cancers, which implies that the form

FAQs

Why is multidrug resistance (MDR) a major obstacle in cancer therapy?

MDR makes cancer cells resistant to anticancer agents that differ functionally and structurally from the drugs originally used. It arises from multiple cellular adaptations such as altered efflux, targets, detoxification, ROS regulation, and more.

How does NRF2 contribute to MDR in cancer cells?

NRF2 can be overexpressed or hyperactivated in cancer cells, promoting survival in ROS-rich environments through redox adaptation. This state is associated with increased proliferation and resistance to chemotherapy.

What is the rationale for using plant-origin NRF2 inhibitors in anticancer therapy?

Since NRF2 plays an important role in MDR acquisition, inhibiting NRF2 may restore or improve chemotherapy effectiveness. The review focuses on current knowledge of plant NRF2 inhibitors and their observed effects on overcoming MDR.

Sep 21, 2026

Uploaded by Skyler