MG624, an α7‐nicotinic receptor antagonist inhibits growth of human small cell lung cancer by induction of p73

Abstract

Small cell lung cancer (SCLC) is characterized by rapid progression, early metastasis and low survival rates. Smoking has been correlated to 90% of all reported SCLC cases suggesting that tobacco components like nicotine contribute to the pathophysiology of this disease. Recent studies showed that SCLC cells have a functional cholinergic loop, and that both acetylcholine and nicotine stimulate SCLC cell growth. We hypothesized that sustained exposure to nicotine stimulates the growth of the human SCLC cell lines via the α7‐nicotinic acetylcholine receptor (nAChR); therefore, α7‐nAChR antagonists should be useful in attenuating the growth of human SCLCs. We tested a panel of α7‐nAChR antagonists for their growth inhibitory effects on DMS114 human SCLC cells. We observed that MG624 displays potent growth‐inhibitory activity on multiple human SCLC cell lines. TUNEL and caspase‐3 cleavage assays showed that MG624 induced robust apoptosis in human SCLC cells. MG624 also suppressed angiogenesis in “Matrigel Assays,” as well as in “Ex vivo rat aortic ring angiogenesis assays.” The apoptotic activity of MG624 was mediated by p73 and the Akt pathway. Our data suggest that MG624 may have potential applications for the treatment of human SCLCs. Funding for our study was supported by the ASPET‐Astellas Foundation, an MU‐ADVANCE Fellowship, Sigma Xi GIAR, and the Flight Attendant Medical Research Institute YCSA Grant.