The Dual Roles of NRF2 in Cancer

Modulating ROS to overcome multidrug resistance in cancer.

Cancer cells first adapt to the microenvironment and then propagate. Mutations in tumor suppressor genes or oncogenes are frequently found in cancer cells. Comprehensive genomic analyses have identified somatic mutations and other alterations in the KEAP1 or NRF2 genes and in well-known tumor suppressor genes or oncogenes, such as TP53, CDKN2A, PTEN, and PIK3CA, in various types of cancer. Aberrant NRF2 activation in cancer cells occurs through somatic mutations in the KEAP1 or NRF2 gene as well as through other mechanisms that disrupt the binding of KEAP1 to NRF2. Unregulated NRF2 confers on cancer cells high-level resistance to anti-cancer drugs and reactive oxygen species (ROS) and directs cancer cells toward metabolic reprogramming. Therefore, NRF2 has been studied as a therapeutic target molecule in cancer. Two strategies have been used to target NRF2 via therapeutic drugs: inhibition of NRF2 and induction of NRF2. NRF2 inhibitors may be effective against NRF2-addicted cancer cells in which NRF2 is aberrantly activated. These inhibitors have not yet been established as NRF2-targeted anti-cancer drugs for the treatment of human cancers. Diagnosis of NRF2 activation could facilitate the use of NRF2 inhibitors for the treatment of patients with NRF2-addicted cancers. Conversely, NRF2 inducers have been used or are being developed for non-cancer diseases. In addition, NRF2 inducers may be useful for cancer chemotherapy in combination with conventional anti-cancer agents or even NRF2 inhibitors.

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The KEAP1–NRF2 System in Cancer

Radioresistance is a major factor leading to the failure of radiotherapy and poor prognosis in tumor patients. Following the application of radiotherapy, the activity of various metabolic pathways considerably changes, which may result in the development of resistance to radiation. Here, we discussed the relationships between radioresistance and mitochondrial and glucose metabolic pathways, aiming to elucidate the interplay between the tumor cell metabolism and radiotherapy resistance. In this review, we additionally summarized the potential therapeutic targets in the metabolic pathways. The aim of this review was to provide a theoretical basis and relevant references, which may lead to the improvement of the sensitivity of radiotherapy and prolong the survival of cancer patients.

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Role of metabolism in cancer cell radioresistance and radiosensitization methods.

Temozolomide (TMZ), an alkylating agent, is widely used for treating primary and recurrent high-grade gliomas. However, the efficacy of TMZ is often limited by the development of resistance. Recently, studies have found that TMZ treatment could induce autophagy, which contributes to therapy resistance in glioma. To enhance the benefit of TMZ in the treatment of glioblastomas, effective combination strategies are needed to sensitize glioblastoma cells to TMZ. In this regard, as autophagy could promote cell survival or autophagic cell death, modulating autophagy using a pharmacological inhibitor, such as chloroquine, or an inducer, such as rapamycin, has received considerably more attention. To understand the effectiveness of regulating autophagy in glioblastoma treatment, this review summarizes reports on glioblastoma treatments with TMZ and autophagic modulators from in vitro and in vivo studies, as well as clinical trials. Additionally, we discuss the possibility of using autophagy regulatory compounds that can sensitive TMZ treatment as a chemotherapy for glioma treatment.

/pdf/targeting-autophagy-to-sensitive-glioma-to-temozolomide-z014a5gdpi.pdf

Guang-Chun Sun

Papers

Chrysin enhances sensitivity of BEL-7402/ADM cells to doxorubicin by suppressing PI3K/Akt/Nrf2 and ERK/Nrf2 pathway