Brusatol Enhances the Radiosensitivity of A549 Cells by Promoting ROS Production and Enhancing DNA Damage.

Xiaohui Sun,Qiang Liu,Qin Wang,Liqing Du,Yan Wang,Chang Xu

doi:10.3390/ijms17070997

Abstract

NF-E2-related factor 2 (Nrf2) has been identified as a master regulatory factor in the protection of cells from oxidative and electrophilic stress. However, overexpression of Nrf2 in lung cancer may cause chemoresistance, as well as radioresistance. In this study, we examined the relationship between radioresistance and Nrf2 protein levels in H1299, A549, and H460 cells, and finally chose the A549 cell line to continue with due to its strong radioresistance and high Nrf2 protein levels. We found that the Nrf2 inhibitor, brusatol, could prevent the increase and accumulation of Nrf2 after exposure to irradiation. Additionally, following treatment with 80 nM brusatol, A549 cells became sensitive to irradiation, suffering severe DNA damage. Combination treatment with brusatol and ionizing radiation (IR) can distinctly increase the level of reactive oxygen species in A549 cells, causing a 1.8-fold increase compared with the control, and a 1.4-fold increase compared with IR alone. In fact, in the treatment with both brusatol and IR, lung cancer cell proliferation is halted, gradually leading to cell death. Because Nrf2 is closely linked to DNA damage repair, inhibiting the function of Nrf2, as in brusatol treatment, may increase the DNA damage caused by radiotherapy or chemotherapy, possibly enhancing the efficacy of chemotherapeutic drugs. Our study is the first to demonstrate brusatol’s ability to enhance the responsiveness of lung cancer cells to irradiation, and its potential application as a natural sensitizer in radiotherapy.

Highlights

Among all cancers, lung cancer has the highest mortality rate worldwide
When exposed to oxidative, electrophilic, or xenobiotic stress, NF-E2-related factor 2 (Nrf2) escapes from Keap1-dependent repression and translocates to the nucleus, where it directs a series of cell protective proteins, such as the antioxidant phase II detoxifying enzymes, by binding to antioxidant response elements (ARE) with small musculoaponeurotic fibrosarcoma protein [11,12]
It has been demonstrated that Nrf2, a major regulator of redox homeostasis, plays an important role in radioresistance and the gain function of Nrf2 in Non-Small-Cell-Lung Carcinoma (NSCLC) cells confers radioresistance

Summary

Introduction

Routine treatment often involves chemotherapy combined with radiotherapy The latter can effectively inhibit cell proliferation and induce cell death in the cancer cells by overproducing reactive oxygen species (ROS) [1,2]. High expression levels of ROS scavenging enzymes, either intrinsic or acquired, can confer radiotherapy resistance [3,4,5]. This greatly affects the clinical outcome, and there is, an urgent need for combination therapies, which could overcome the major resistance. Novel drugs targeting Nrf might be used as an effective strategy to enhance the radiosensitivity of lung cancer cells, improving clinical outcomes for patients

Objectives

Methods

Results

Conclusion