title: Bombesin/gastrin-releasing peptide receptor antagonists increase the ability of histone deacetylase inhibitors to reduce lung cancer proliferation.
abstract: 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.
authors.affiliation: Department of Health and Human Services, Office of the Director, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA.
authors.forename: Terry W
authors.initials: TW
authors.lastname: Moody
authors.forename: Tomoo
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Yang
authors.initials: Y
authors.lastname: Kang
authors.forename: Sonia
authors.initials: S
authors.lastname: Jakowlew
authors.forename: Daniel
authors.initials: D
authors.lastname: Chan
authors.forename: Robert T
authors.initials: RT
authors.lastname: Jensen
mesh_terms: D000818:Animals; D001549:Benzamides / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D005562:Formazans / Q000378:metabolism; D016147:Genes, Tumor Suppressor; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology*; D018004:Receptors, Bombesin / Q000037:antagonists & inhibitors*; D013778:Tetrazolium Salts / Q000378:metabolism
chemical_list: D001549:Benzamides; D005562:Formazans; D056572:Histone Deacetylase Inhibitors; D007211:Indoles; D011725:Pyridines; D018004:Receptors, Bombesin; D013778:Tetrazolium Salts; C118739:entinostat; C079782:MTT formazan; C116774:PD 176252