pd-176252 and Lung-Neoplasms

The effects of a bombesin/gastrin releasing peptide (BB/GRP) receptor antagonist, PD176252, and histone deacetylase (HDAC) inhibitor, MS-275, were investigated on human lung cancer cell lines. Using the MTT assay, PD176252 and MS-275 inhibited the proliferation of NCI-H1299 cells with IC50 values of 7 and 5 microg/mL, respectively. Using MS-275 and PD176252 together, the ability to inhibit lung cancer cellular growth increased significantly. The combination index for MS-275 and PD176252 was <0.2, indicating that the compounds are highly synergistic in inhibiting lung cancer cellular growth. Also, MS-275 and PD176252 together strongly inhibited the clonal growth of NCI-H345 or NCI-H1299 cells. MS-275 had little effect on the expression of lung cancer cellular GRP or GRP receptors, but increased expression of transforming growth factor-beta receptor II (TGF-beta RII). These results indicate that GRP receptor antagonists may potentiate the action of histone deacetylase inhibitors on lung cancer cellular proliferation by increasing expression of tumor suppressor genes.

Topics: Animals; Benzamides; Cell Line, Tumor; Cell Proliferation; Formazans; Genes, Tumor Suppressor; Histone Deacetylase Inhibitors; Humans; Indoles; Lung Neoplasms; Pyridines; Receptors, Bombesin; Tetrazolium Salts

The ability of nonpeptide antagonists to interact with gastrin releasing peptide receptors on lung cancer cells was investigated. PD176252 (3-(1H-Indol-3-yl)-N-[1-(5-methoxy-pyridin-2-yl)-cyclohexylmethyl]-2-methyl-2-[3-(4-nitro-phenyl)-ureido]-propionamide) and PD168368 (3-(1H-Indol-3-yl)-2-methyl-2-[3(4-nitro-phenyl)-ureido]-N-(1-pyridin-2-yl-cyclohexylmethyl)-propionamide) inhibited specific 125I-gastrin releasing peptide binding to NCI-H1299 cells with IC50 values of 20 and 1500 nM, respectively. Similar binding results were obtained using NCI-H157, H345 and N592 human lung cancer cells. PD176252 inhibited the ability of 1 nM bombesin to cause elevation of cytosolic calcium in Fura-2 loaded NCI-H345 or H1299 cells, whereas it had no effect on basal cytosolic calcium. PD176252 antagonized the ability of 10 nM bombesin to cause elevation of c-fos mRNA in NCI-H1299 cells. Also, PD176252 inhibited the ability of 100 nM bombesin to cause tyrosine phosphorylation of focal adhesion kinase in NCI-H1299 cells. Using a [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide] assay, PD176252 was more potent than PD168368 at inhibiting NCI-H1299 proliferation. Also, 1 microM PD176252 significantly inhibited lung cancer colony number in vitro. PD176252 in a dose-dependent manner inhibited NCI-H1299 xenograft growth in nude mice in vivo. These results indicate that PD176252 is a gastrin releasing peptide receptor antagonist, which inhibits the proliferation of lung cancer cells.

Topics: Animals; Calcium; Cell Division; Cytosol; Dose-Response Relationship, Drug; Female; Humans; Indoles; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Pyridines; Receptors, Bombesin; Tumor Cells, Cultured; Xenograft Model Antitumor Assays