Cancers, Vol. 13, Pages 1885: KEAP1 Is Required for Artesunate Anticancer Activity in Non-Small-Cell Lung Cancer

Cancers, Vol. 13, Pages 1885: KEAP1 Is Required for Artesunate Anticancer Activity in Non-Small-Cell Lung Cancer Cancers doi: 10.3390/cancers13081885 Authors: Kristen S. Hill Anthony McDowell J. Robert McCorkle Erin Schuler Sally R. Ellingson Rina Plattner Jill M. Kolesar Artesunate is the most common treatment for malaria throughout the world. Artesunate has anticancer activity likely through the induction of reactive oxygen species, the same mechanism of action utilized in Plasmodium falciparum infections. Components of the kelch-like ECH-associated protein 1 (KEAP1)/nuclear factor erythroid 2-related factor 2 (NRF2) pathway, which regulates cellular response to oxidative stress, are mutated in approximately 30% of non-small-cell lung cancers (NSCLC); therefore, we tested the hypothesis that KEAP1 is required for artesunate sensitivity in NSCLC. Dose response assays identified A549 cells, which have a G333C-inactivating mutation in KEAP1, as resistant to artesunate, with an IC50 of 23.6 µM, while H1299 and H1563 cells were sensitive to artesunate, with a 10-fold lower IC50. Knockdown of KEAP1 through siRNA caused increased resistance to artesunate in H1299 cells. Alternatively, the pharmacological inhibition of NRF2, which is activated downstream of KEAP1 loss, by ML385 partially restored sensitivity of A549 cells to artesunate, and the combination of artesunate and ML385 was synergistic in both A549 and H1299 cells. These findings demonstrate that KEAP...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research