Dietary Phytochemicals Targeting Nrf2 to Enhance the Radiosensitivity of Cancer

Abstract

Nowadays, cancer has become the second leading cause of death worldwide. Radiotherapy (RT) is the mainstay in management of carcinoma; however, overcoming radioresistance remains a great challenge to successfully treat cancer. Nrf2 is a key transcription factor that is responsible for maintaining cellular redox homeostasis. Activation of Nrf2 signaling pathway could upregulate multifarious antioxidant and detoxifying enzymes, further scavenging excessive reactive oxygen species (ROS). Despite its cytoprotective roles in normal cells, it could also alleviate oxidative stress and DNA damage caused by RT in cancer cells, thus promoting cancer cell survival. Accumulating evidence indicates that overactivation of Nrf2 is associated with radioresistance; therefore, targeting Nrf2 is a promising strategy to enhance radiosensitivity. Dietary phytochemicals coming from natural products are characterized by low cost, low toxicity, and general availability. Numerous phytochemicals are reported to regulate Nrf2 and intensify the killing capability of RT through diverse mechanisms, including promoting oxidative stress, proapoptosis, and proautophagy as well as inhibiting Nrf2-mediated cytoprotective genes expression. This review summarizes recent advances in radiosensitizing effects of dietary phytochemicals by targeting Nrf2 and discusses the underlying mechanisms, including N6-methyladenosine (m6A) modification of Nrf2 mediated by phytochemicals in cancer.

Delicaflavone Represses Lung Cancer Growth by Activating Antitumor Immune Response through N6-Methyladenosine Transferases and Oxidative Stress

“…Mechanistically, we revealed that DLL reduced Stat1 and Irf1 m6A modification abundance by inhibiting Mettl3 and Mettl14, thereby upregulating CCL5, CXCL9, and CXCL10 and inducing oxidative stress. Studies have showed that phytochemicals from natural products induce the accumulation of ROS by damaging DNA biomolecules and triggering cell death-related signaling pathways, including m6A modification [ 34 ]. m6A alteration is critical in the creation of tumor immune microenvironment variety and complexity in lung cancer [ 35 ].…”

The Self-Administered Use of Complementary and Alternative Medicine (CAM) Supplements and Antioxidants in Cancer Therapy and the Critical Role of Nrf-2—A Systematic Review

“…As such, Nrf-2 downregulation or inhibition of nuclear translocation is a main goal of adjuvant therapy with phytochemicals. Cell culture experiments with Nrf-2 inhibitors show an increase in cellular ROS and reduced cell proliferation due to enhanced apoptosis [ 194 ]. Interestingly, the Nrf-2 activator EGCG induced the nuclear import of Nrf-2 and enhanced apoptosis and autophagy in HCT-116 colon cancer cells [ 195 ].…”

The Therapeutic Potential of Kaemferol and Other Naturally Occurring Polyphenols Might Be Modulated by Nrf2-ARE Signaling Pathway: Current Status and Future Direction

“…Natural products based phytochemicals increase cancer cell death primarily by regulating Nrf2 [10], leading to pro-autophagy, oxidative stress, pro-apoptosis and inhibition of expression of cytoprotective genes [11]. Several phytochemicals exert their anticancer or chemo preventive role by Nrf2 modulation [12]. These include quercetin, curcumin, and resveratrol [13].…”