Induction of apoptosis by a short-chain neuropeptide analog in small cell lung cancer

Small cell lung cancer (SCLC) cells express a variety of neuropeptides whic h act as autocrine growth factors. Although several neuropeptide analogs ha ve been reported to antagonize SCLC proliferation, the development of these compounds has bren limited by their low potency and the cytostatic nature of their effects. In the present study we evaluated the cytotoxic activity of four short-chain substance P analogs (NY3460, NY3238[-pHOPA], NY3238[Phe (1)], NY3238[Lys(5)]) against a panel of five SCLC cell lines. NY3460 was t he most potent compound in all five SCLC cell lines (IC50 = 2.8-3.7 mu M) a s assessed by a MTT grow-th inhibitory assay. NY3238[Phe(1)] was also relat ively active in all cell lines (IC50 = 3.5-11.2 mu M), while NY3238[Lys(5)] and NY3238[-pHOPA] were substantially less active. NY3460 was the only age nt ro induce an increase in the percentage of cells with subdiploid DNA con tent suggestive of apoptosis by flow cytometric DNA content analysis. The i nduction of apoptosis was confirmed by fluorescent microscopy in NCI-H69, N CI-H82, NCI-H446, and NCI-H510 cells after exposure to 5.0 mu M NY3460 for 48 h. These findings suggest that NY3460 is a relatively potent cytotoxic i nhibitor of SCLC growth, and that short-chain neuropeptide analogs deserve further evaluation as anti-SCLC agents. (C) 1998 Elsevier Science Inc.