Camptothecin suppresses NRF2–ARE activity and sensitises hepatocellular carcinoma cells to anticancer drugs

Abstract

Background:Resistance to chemotherapy is a major obstacle in the treatment of human hepatocellular carcinoma (HCC). Despite playing an important role in chemoprevention, nuclear factor erythroid 2-related factor 2 (NRF2) also contributes to chemo- and radio-resistance. The current study focusses on camptothecin as a novel NRF2 inhibitor to sensitise HCC to chemotherapy.Methods:The expression and transcriptional activity of NRF2 in human HCC biopsies and camptothecin-treated culture cells were determined using immunostaining, western blot, reverse-transcription quantitative real-time PCR (RT–qPCR) and luciferase reporter assay. The effect of camptothecin on chemosensitivity of cancer cells was assessed in vitro and in xenografts.Results:The expression and transcriptional activity of NRF2 were substantially elevated in HCC biopsies compared with corresponding adjacent tissues, and positively correlated with serum α-fetoprotein, a clinical indicator of pathological progression. In searching chemicals targeting NRF2 for chemotherapy, we discovered that camptothecin is a potent NRF2 inhibitor. Camptothecin markedly suppressed NRF2 expression and transcriptional activity in different types of cancer cells including HepG2, SMMC-7721 and A549. As a result, camptothecin sensitised these cells to chemotherapeutic drugs in vitro and in xenografts.Conclusions:Camptothecin is a novel NRF2 inhibitor that may be repurposed in combination with other chemotherapeutics to enhance their efficacy in treating high NRF2-expressing cancers.

UVA Irradiation Enhances Brusatol‐Mediated Inhibition of Melanoma Growth by Downregulation of the Nrf2‐Mediated Antioxidant Response

“…These results indicate that cotreatment in A375 inhibits/AKT signaling while inhibiting Nrf2 expression. Similar results were obtained with camptothecin as another potential inhibitor of Nrf2 (data not shown) [ 45 , 46 ].…”

Identification of diagnostic and prognostic biomarkers, and candidate targeted agents for hepatitis B virus‑associated early stage hepatocellular carcinoma based on RNA‑sequencing data

“…Additionally, resveratrol, apigenin, luteolin and menadione have been demonstrated to display good therapeutic effects in animal models (45,(78)(79)(80). Camptothecin, chrysin and MS-275 have only been studied in vivo or in cell experiments, but may have potential to treat HCC (81)(82)(83). Other small molecular compounds have not yet been demonstrated to have effectiveness against HCC, and therefore further research is required.…”

Nrf2 in Neoplastic and Non-Neoplastic Liver Diseases

“…Zhou and colleagues demonstrated that Nrf2 expression increased when the BEL-7402 cell line was exposed to the 5-Fluorouracil, suggesting an involvement of this transcription factor in HCC chemoresistance [ 160 ]. The use of Camptotechin, a Nrf2 inhibitor, enhanced the sensitivity of HCC cell lines to chemotherapeutic agents, impairing cancer cell viability [ 161 ]. Furthermore, inhibition of Nrf2 through Apigenin reversed the drug-resistant phenotype.…”

“…However, Halofuginone, similar to Brusatol, is not a specific Nrf2 inhibitor as it represses global protein synthesis, thus rapidly depleting Nrf2. Camptotechin, another alkaloid isolated from the Chinese tree Camptotheca acuminate, inhibits Nrf2 activity in HCC cells, reverting chemoresistance [ 161 ]. However, its mechanism of action is not clear, as no direct effect in promoting Nrf2 protein degradation could be provided.…”