IDH-Inhibiting Small Molecule DTDQ Inhibits Migration and Invasion of A549 Human Non-Small-Cell Lung Cancer Cells via Sequential Inactivation Of ERK and P38 Signaling Pathways

Abstract

Migration and invasion are two core processes during cancer metastasis, and several signaling pathways have been shown to be involved. A key regulator of metastasis is the mitogen-activated protein kinase signaling pathway. Here, we report that the small molecule, 6,7-dimethyl-4-(3,4,5-trimethoxyphenyl)-3,4-dihydroquinolin-2(1H)-one, inhibited isocitrate dehydrogenase activity and had anti-metastatic effects in A549 human non-small-cell lung cancer cells. 6,7-dimethyl-4-(3,4,5-trimethoxyphenyl)-3,4-dihydroquinolin-2(1H)-one induced sequential inactivation of the extracellular signal-regulated kinases and p38 signaling pathways, both representative mitogen-activated protein kinase family members. We also found that 6,7-dimethyl-4-(3,4,5-trimethoxyphenyl)-3,4-dihydroquinolin-2(1H)-one suppressed the transcription factor c-Myc, a regulator of cancer metastasis. This led to selective attenuation of matrix metalloproteinase-2 and subsequent suppression of migration and invasion in A549 non-small-cell lung cancer cells. 6,7-dimethyl-4-(3,4,5-trimethoxyphenyl)-3,4-dihydroquinolin-2(1H)-one also suppressed metastasis in H1299 non-small-cell lung cancer cells, suggesting that the effects of 6,7-dimethyl-4-(3,4,5-trimethoxyphenyl)-3,4-dihydroquinolin-2(1H)-one are not limited to A549 non-small-cell lung cancer cells. We therefore propose that the antimetastatic effects of 6,7-dimethyl-4-(3,4,5-trimethoxyphenyl)-3,4-dihydroquinolin-2(1H)-one are due to sequential inactivation of the extracellular signal-regulated kinases and p38 signaling pathways.