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Lung Cancer (Amsterdam, Netherlands) May 2010The effects of dithiolethione modified valproate, diclofenac and sulindac on non-small cell lung cancer (NSCLC) cells were investigated. Sulfur(S)-valproate and...
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
PubMed: 19628293
DOI: 10.1016/j.lungcan.2009.06.012 -
British Journal of Pharmacology May 2007Angiogenesis involves multiple signaling pathways that must be considered when developing agents to modulate pathological angiogenesis. Because both cyclooxygenase...
BACKGROUND AND PURPOSE
Angiogenesis involves multiple signaling pathways that must be considered when developing agents to modulate pathological angiogenesis. Because both cyclooxygenase inhibitors and dithioles have demonstrated anti-angiogenic properties, we investigated the activities of a new class of anti-inflammatory drugs containing dithiolethione moieties (S-NSAIDs) and S-valproate.
EXPERIMENTAL APPROACH
Anti-angiogenic activities of S-NSAIDS, S-valproate, and the respective parent compounds were assessed using umbilical vein endothelial cells, muscle and tumor tissue explant angiogenesis assays, and developmental angiogenesis in Fli:EGFP transgenic zebrafish embryos.
KEY RESULTS
Dithiolethione derivatives of diclofenac, valproate, and sulindac inhibited endothelial cell proliferation and induced Ser(78) phosphorylation of hsp27, a known molecular target of anti-angiogenic signaling. The parent drugs lacked this activity, but dithiolethiones were active at comparable concentrations. Although dithiolethiones can potentially release hydrogen sulphide, NaSH did not reproduce some activities of the S-NSAIDs, indicating that the dithioles regulate angiogenesis through mechanisms other than release of H(2)S. In contrast to the parent drugs, S-NSAIDs, S-valproate, NaSH, and dithiolethiones were potent inhibitors of angiogenic responses in muscle and HT29 tumor explants assessed by 3-dimensional collagen matrix assays. Dithiolethiones and valproic acid were also potent inhibitors of developmental angiogenesis in zebrafish embryos, but the S-NSAIDs, remarkably, lacked this activity.
CONCLUSIONS AND IMPLICATION
S-NSAIDs and S-valproate have potent anti-angiogenic activities mediated by their dithiole moieties. The novel properties of S-NSAIDs and S-valproate to inhibit pathological versus developmental angiogenesis suggest that these agents may have a role in cancer treatment.
Topics: Anethole Trithione; Angiogenesis Inhibitors; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Proliferation; Endothelial Cells; HSP27 Heat-Shock Proteins; Heat-Shock Proteins; Humans; Mice; Mice, Inbred C57BL; Phosphorylation; Solubility; Valproic Acid; Zebrafish
PubMed: 17351657
DOI: 10.1038/sj.bjp.0707198 -
International Journal of Cancer 2001Lens epithelium disorganization, glutathione (GSH) depletion, and epithelial cell death have been incriminated in the cytopathogenic mechanisms that lead to cataract...
Lens epithelium disorganization, glutathione (GSH) depletion, and epithelial cell death have been incriminated in the cytopathogenic mechanisms that lead to cataract formation following UVB and x-ray exposures. The objective of this study was to determine the in vitro capacity of the aminothiol WR-1065, the active metabolite of amifostine, and anetholedithiolethione (ADT or Sulfarlem) to protect bovine lens epithelial cells against x-ray irradiation. WR-1065 and ADT were used at a concentration of 20 microM. A single dose of 10 Gy was delivered at a rate of 2 Gy/min. Fluorimetric assays were then performed using a neutral red probe to evaluate cell viability, a Hoechst 33342 probe (HO) to evaluate nuclear condensation and apoptosis, and a monobromobimane probe to estimate the intracellular GSH pool. Twenty-four hours after x-ray exposure, cells pretreated with WR-1065 showed increased GSH levels, improved cell viability, and decreased HO fluorescence in addition to a lesser proportion of cells with apoptotic nuclear modifications. Between 72 and 120 hr postirradiation, ADT-pretreated cells also showed increased intracellular GSH levels and cell viability and decreased HO fluorescence and apoptotic cell morphology. This in vitro study demonstrates that WR-1065 and ADT protects lens epithelial cells from x-ray injury; thus, ADT and amifostine are appropriate candidates for clinical trials in humans. They are currently used in preventing radiation-induced xerostomia and should be further tested in the prevention of late radiation-induced ocular complications such as sicca syndrome and cataract.
Topics: Amifostine; Anethole Trithione; Animals; Apoptosis; Benzimidazoles; Cattle; Cell Death; Cell Membrane; Cell Nucleus; Cell Survival; Cells, Cultured; Dose-Response Relationship, Radiation; Epithelial Cells; Flow Cytometry; Glutathione; Lens, Crystalline; Mercaptoethylamines; Microscopy, Fluorescence; Radiation-Protective Agents; Spectrometry, Fluorescence; Time Factors; Ultraviolet Rays; X-Rays
PubMed: 11992383
DOI: 10.1002/ijc.10346