cay-10404 and Lung-Neoplasms

The effects of dithiolethione modified valproate, diclofenac and sulindac on non-small cell lung cancer (NSCLC) cells were investigated. Sulfur(S)-valproate and S-diclofenac at 1 microg/ml concentrations significantly reduced prostaglandin (PG)E(2) levels in NSCLC cell lines A549 and NCI-H1299 as did the COX-2 inhibitor DuP-697. In vitro, S-valproate, S-diclofenac and S-sulindac half-maximally inhibited the clonal growth of NCI-H1299 cells at 6, 6 and 15 microg/ml, respectively. Using the MTT assay, 10 microg/ml S-valproate, NO-aspirin and Cay10404, a selective COX-2 inhibitor, but not SC-560, a selective COX-1 inhibitor, inhibited the growth of A549 cells. In vivo, 18mg/kg i.p. of S-valproate and S-diclofenac, but not S-sulindac, significantly inhibited A549 or NCI-H1299 xenograft proliferation in nude mice, but had no effect on the nude mouse body weight. The mechanism by which S-valproate and S-diclofenac inhibited the growth of NSCLC cells was investigated. Nitric oxide-aspirin but not S-valproate caused apoptosis of NSCLC cells. By Western blot, S-valproate and S-diclofenac increased E-cadherin but reduced vimentin and ZEB1 (a transcriptional suppressor of E-cadherin) protein expression in NSCLC cells. Because S-valproate and S-diclofenac inhibit the growth of NSCLC cells and reduce PGE(2) levels, they may prove beneficial in the chemoprevention and/or therapy of NSCLC.

Topics: Anethole Trithione; Animals; Cadherins; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Cyclooxygenase Inhibitors; Diclofenac; Dinoprostone; Gene Expression Regulation, Neoplastic; Humans; Isoxazoles; Lung Neoplasms; Mice; Mice, Nude; Neoplasm Transplantation; Pyrazoles; Sulfones; Valproic Acid

Lung cancer is the most common cause of cancer death in men and women worldwide. The mechanism of cell death induced by CAY10404, a highly selective cyclooxygenase-2 inhibitor, was evaluated in three non-small cell lung cancer (NSCLC) cell lines (H460, H358, H1703).. To measure the effects of CAY10404 on proliferation of NSCLC cells, 3 x 10(3) cells/well were plated in 96-well plates and allowed to adhere overnight at 37 degrees C. After treatment with CAY10404 for 3 days, cell proliferation was measured by the 3- (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. In the H460 NSCLC cells, evidence of apoptosis was sought using the terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick end labelling (TUNEL) assay and western blot analysis.. Treatment with CAY10404 in the range of 10-100 microM caused dose-dependent growth inhibition, with an average 50% inhibitory concentration (IC(50)) of 60-100 micromol/L, depending on the cell line. Western blot analysis of CAY10404-treated cells showed cleavage of poly (ADP-ribose) polymerase (PARP) and procaspase-3, signifying caspase activity and apoptotic cell death. CAY10404 treatment inhibited the phosphorylation of Akt, glycogen synthase kinase-3beta and extracellular signal-regulated kinases 1/2 in H460 and H358 cells.. These results suggest that CAY10404 is a potent inducer of apoptosis in NSCLC cells, and that it may act by suppressing multiple protein kinase B/Akt and mitogen-activated protein kinase pathways.

Topics: Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cyclooxygenase 2 Inhibitors; Dose-Response Relationship, Drug; Humans; Isoxazoles; Lung Neoplasms; Mitogen-Activated Protein Kinase Kinases; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Sulfones