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Salinomycin Overcomes Pemetrexed Resistance in Non-Small Cell Lung Cancer Cells by Inhibiting Epithelial-Mesenchymal Transition
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A2690 - Salinomycin Overcomes Pemetrexed Resistance in Non-Small Cell Lung Cancer Cells by Inhibiting Epithelial-Mesenchymal Transition
Author Block: K. Hwang, S. Oh, H. Kim, E. Jeong; Wonkwnag University Hospital, Iksan, Korea, Republic of.
Background:Pemetrexed is a multitarget antifolate for the treatment of advanced non-squamous NSCLC. Although pemetrexed as a maintenance therapy after cisplatin-based doublet chemotherapy increases survival, development of acquired resistance is almost inevitable. Salinomycin has reported antitumor activity, but it is unknown whether salinomycin can decrease pemetrexed resistance. This study was designed to investigate overcoming pemetrexed resistance by inhibiting epithelial-mesenchymal transition (EMT) using salinomycin. Methods:We developed an in vitro model of acquired resistance to pemetrexed by continuously treating A549 and H460 with escalating doses. The effects of salinomycin on EMT and lung cancer migration and invasion in pemetrexed resistance (PR) cells were examined by western blotting and confocal microscopy. The anti-tumor effects of salinomycin on tumor growth in vivo also evaluated. Results:Morphological changes that are persistent with the acquisition of the EMT phenotype showed in A549PRand H460PR cells. Addition of salinomycin to pemetrexed inhibited PR-induced EMT, as indicated by upregulation of E-cadherin, and downregulation of mesenchymal markers and transcriptional factors. Moreover, salinomycin could suppress migration and invasion of A549PR and H460PR cells. In vivo, salinomycin also augmented the inhibitory effects of pemetrexed on tumor growth of A549PR. Conclusions:Salinomycin may overcome pemetrexed resistance in NSCLC via inhibiting EMT and suppressing lung cancer cell migration and invasion.
Author Block: K. Hwang, S. Oh, H. Kim, E. Jeong; Wonkwnag University Hospital, Iksan, Korea, Republic of.
Background:Pemetrexed is a multitarget antifolate for the treatment of advanced non-squamous NSCLC. Although pemetrexed as a maintenance therapy after cisplatin-based doublet chemotherapy increases survival, development of acquired resistance is almost inevitable. Salinomycin has reported antitumor activity, but it is unknown whether salinomycin can decrease pemetrexed resistance. This study was designed to investigate overcoming pemetrexed resistance by inhibiting epithelial-mesenchymal transition (EMT) using salinomycin. Methods:We developed an in vitro model of acquired resistance to pemetrexed by continuously treating A549 and H460 with escalating doses. The effects of salinomycin on EMT and lung cancer migration and invasion in pemetrexed resistance (PR) cells were examined by western blotting and confocal microscopy. The anti-tumor effects of salinomycin on tumor growth in vivo also evaluated. Results:Morphological changes that are persistent with the acquisition of the EMT phenotype showed in A549PRand H460PR cells. Addition of salinomycin to pemetrexed inhibited PR-induced EMT, as indicated by upregulation of E-cadherin, and downregulation of mesenchymal markers and transcriptional factors. Moreover, salinomycin could suppress migration and invasion of A549PR and H460PR cells. In vivo, salinomycin also augmented the inhibitory effects of pemetrexed on tumor growth of A549PR. Conclusions:Salinomycin may overcome pemetrexed resistance in NSCLC via inhibiting EMT and suppressing lung cancer cell migration and invasion.
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