α7-Nicotinic acetylcholine receptor antagonist QND7 suppresses non-small cell lung cancer cell proliferation and migration via inhibition of Akt/mTOR signaling

Abstract

Lung cancer, one of the most commonly found carcinoma type, has the highest mortality rate in cancer patients worldwide. Therapeutic interventions targeting to lung cancer become remaining the world significant challenge. Recently, the α7-nicotinic acetylcholine receptor (α7-nAChR) was reported to play an important role in the mechanism underlying lung cancer progression, being intriguing drug target for lung cancer therapy. Hence, the top four α7-nAChR antagonists (QND7, PPRD10, PPRD11 and PPRD12) among our previously developed ligands were proceeded to the in vitro anti-cancer evaluations in non-small cell lung cancer (NSCLC) cell lines (H460 and A549). In this study, we found that QND7 exhibited the highest cytotoxic effect and induced cell apoptosis in both cell lines at a level comparable to cisplatin, whereas the PPRD compounds showed much lower cytotoxicity. Low doses of QND7 and PPRD11 were able to suppress H460 and A549 cell proliferation, whereas PPRD10 and PPRD12 were considered ineffective. In an in vitro wound healing assay, QND7-treatment showed the greatest suppression of H460 and A549 cell migration. The variations in the anti-cancer activities of PPRD compounds might be, at least in part of, their non-selective antagonisms to serotonin receptor (5-HT3) and α4β2-nAChR. Further investigation revealed that QND7 was able to minimize protein kinase B/mammalian target of rapamycin (Akt/mTOR) activity, in correlating to its anti-cancer effects. These findings warrant QND7 for further preclinical evaluation and demonstrate the potential of α7-nAChR as cancer drug target.

Keywords: Antagonist; Cell death; Cell migration; Cell proliferation; Non-small cell lung cancer; α7-nicotinic acetylcholine receptor.