SR48692 is a neurotensin receptor antagonist which inhibits the growth of small cell lung cancer cells

Neurotensin (NT) is an autocrine growth factor for some small cell lung cancer (SCLC) cells. In this communication, the effects of a non-peptide NT receptor antagonist, SR48692, were investigated using SCLC cells. ³H-SR48692 bound with high affinity (IC₅₀ = 20 nM) to NCI-H209 cells. Also, NT and SR48692 inhibited specific ¹²⁵I-NT binding with high affinity (IC₅₀ values of 2 and 200 nM). In contrast, the NT₂ receptor agonist, levocabastine, had little effect on specific ¹²⁵I-NT binding, second messenger production and proliferation using NCI-H209 cells. SR48692 (5 μM) antagonized the ability of NT (10 nM) to cause elevated cytosolic Ca²⁺ in Fura-2 AM loaded NCI-H209 cells. SR48692 antagonized the ability of NT to cause elevation of c-fos mRNA in these cells. Using a MTT proliferation assay, SR48692 inhibited NCI-H209 and H345 proliferation in a concentration-dependent manner. Using a clonogenic assay, 1 μM SR48692, reduced NCI-H209 colony number. Also, SR48692 (0.4 mg/kg per day) inhibited NCI-H209 xenograft proliferation in nude mice. These results suggest that SR48692 is a NT₁ receptor antagonist which inhibits SCLC growth.