Kaempferol inhibits Nrf2 signalling pathway via downregulation of Nrf2 mRNA and induces apoptosis in NSCLC cells

Chemoprevention failure is considered to be the most emerging problem that makes non-small cell lung cancer (NSCLC) as one of the deadliest malignancies in the world. In NSCLC cells, Nuclear factor erythmid 2-related factor 2 (Nrf2), a redox sensitive transcription factor, promotes cancer cell survival and fosters mechanism for drug resistance. Here we report identification of Kaempfeml, a dietary flavonoid, as a potent Nrf2 inhibitor using Nrf2 reporter assay in NSCLC cells (A549 and NCIH460). Kaempfeml selectively reduces Nrf2 mRNA and protein levels and lower level of nuclear Nrf2 downregulates transcription of Nrf2 target genes (NQO1, HO1, AKR1C1 and GST). Kaempferol (25 mu M) mediated downregulation of GST, NQO1 and HOl expression is also observed even after stimulation of Nrf2 by tert-butylhydroquinone (tBHQ). Again, Kaempferol incubation does not change the levels of NF kappa Bp65 and phospho NF kappa Bp65, suggesting it hampers Nrf2 signalling pathway in these cells. Nrf2 inhibition by Kaempferol induces ROS accumulation after 48 h of treatment and makes NSCLC cells sensitive to apoptosis at physiological concentration. Taken together, our study demonstrates that Kaempferol is a potent inhibitor of Nrf2 and can be used as a natural sensitizer and anti-cancer agent for lung cancer therapeutics.

Automated summary

Kaempferol has been identified as a potent inhibitor of Nrf2, reducing the expression of Nrf2 and its target genes in NSCLC cells. Additionally, it induces ROS accumulation and sensitizes the cells to apoptosis.