Abstract
Non-small cell lung cancer (NSCLC)-carrying specific epidermal growth factor receptor (EGFR) mutations can be effectively treated by a tyrosine kinase inhibitor such as gefitinib. However, the inevitable development of acquired resistance leads to the eventual failure of therapy. In this study, we show the combination effect of omega-3 fatty acid-enriched fish oil (FO) and selenium (Se) on reversing the acquired gefitinib-resistance of HCC827 NSCLC cells. The gefitinib-resistant subline HCC827GR possesses lowered proapoptotic CHOP (CCAAT/enhancer-binding protein homologous protein) and elevated cytoprotective GRP78 (glucose regulated protein of a 78 kDa molecular weight) endoplasmic reticulum (ER) stress response elements, and it has elevated β-catenin and cyclooxygenase-2 (COX-2) levels. Combining FO and Se counteracts the above features of HCC827GR cells, accompanied by the suppression of their raised epithelial-to-mesenchymal transition (EMT) and cancer stem markers, such as vimentin, AXL, N-cadherin, CD133, CD44, and ABCG2. Accordingly, an FO and Se combination augments the gefitinib-mediated growth inhibition and apoptosis of HCC827GR cells, along with the enhanced activation of caspase -3, -9, and ER stress-related caspase-4. Intriguingly, gefitinib further increases the elevated ABCG2 and cancer stem-like side population in HCC827GR cells, which can also be diminished by the FO and Se combination. The results suggest the potential of combining FO and Se in relieving the acquired resistance of NSCLC patients to targeted therapy.
Highlights
Non-small cell lung cancer (NSCLC) constitutes more than 80% of lung cancers, which is the leading cause of cancer death worldwide [1,2]
After observing the elevated epithelial-to-mesenchymal transition (EMT) and cancer stem cell features of HCC827GR cells shown in Figures 2 and 3, we examined if the fish oil (FO) and Se combination diminished these features when reversing their resistance to gefitinib
As shown in Scheme 1, our previous study showed the opposite regulation of CHOP and GRP78 and the suppression of β-catenin and COX-2 by FO combined with Se in NSCLC cells [31]
Summary
Non-small cell lung cancer (NSCLC) constitutes more than 80% of lung cancers, which is the leading cause of cancer death worldwide [1,2]. A subset of NSCLC-carrying specific genetic mutations of epidermal growth factor receptor (EGFR) can be effectively treated by EGFR tyrosine kinase inhibitor (TKI)-mediated targeted therapy. The two most commonly (>90%) characterized EGFR-activating mutations conferring sensitivity to EGFR-TKIs are small in-frame deletions in exon 19 First-generation EGFR-TKIs, such as gefitinib and erlotinib, have exhibited significant effects in prolonging the disease-free survival of NSCLC patients whose tumors harbor. Most patients who initially respond to EGFR-TKIs eventually acquire resistance within 9–14 months [6], leading to the failure of therapy. Various mechanisms have been discovered to be involved in the acquired resistance to EGFR-TKI, including secondary EGFR T790M
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