Dithiolethione modified valproate and diclofenac increase E-cadherin expression and decrease proliferation of non-small cell lung cancer cells.
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.
Moody
Terry W
TW
National Cancer Institute, Office of the Director, Center for Cancer Research, Bethesda, MD 20892-1500, USA. moodyt@mail.nih.gov
Switzer
Christopher
C
Santana-Flores
Wilmarie
W
Ridnour
Lisa A
LA
Berna
Marc
M
Thill
Michelle
M
Jensen
Robert T
RT
Sparatore
Anna
A
Del Soldato
Piero
P
Yeh
Grace C
GC
Roberts
David D
DD
Giaccone
Giuseppe
G
Wink
David A
DA
D000781:Anethole Trithione / Q000378:metabolism; D000818:Animals; D015820:Cadherins / Q000096:biosynthesis* / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004008:Diclofenac / Q000737:chemistry / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011720:Pyrazoles / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology; D014635:Valproic Acid / Q000737:chemistry / Q000494:pharmacology*
C501048:3-(4-methylsulfonylphenyl)-4-phenyl-5-trifluoromethylisoxazole; D015820:Cadherins; D016861:Cyclooxygenase Inhibitors; D007555:Isoxazoles; D011720:Pyrazoles; C115461:SC 560; D013450:Sulfones; D004008:Diclofenac; D014635:Valproic Acid; D015232:Dinoprostone; D000781:Anethole Trithione