Bombesin/gastrin-releasing peptide receptor antagonists increase the ability of histone deacetylase inhibitors to reduce lung cancer proliferation.
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.
Moody
Terry W
TW
Department of Health and Human Services, Office of the Director, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA.
Nakagawa
Tomoo
T
Kang
Yang
Y
Jakowlew
Sonia
S
Chan
Daniel
D
Jensen
Robert T
RT
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
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