Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:2.7.11.22 (
cdc2
)
8,319
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Therapeutic options to inhibit growth of human NETs of the GEP system are limited. Since NSAIDs might provide an antiproliferative treatment alternative with acceptable toxicity, we examined the effects of different NSAIDs on growth and survival in a representative set of human GEP
NET
cell lines. Growth and apoptosis were determined based on cell numbers, cell-cycle analyses, kinase assays, DNA fragmentation and PARP cleavage. Expression of COX and cell cycle-regulatory molecules was examined by immunoblotting and reporter gene assays. Depending on the drug and cell line investigated, NSAID treatment resulted in profound growth inhibition of GEP
NET
cells. Growth-inhibitory effects were achieved with either COX-2 selective (NS398) or unselective (indomethacin, sulindac) compounds. Cell-cycle analyses documented a G1 arrest in NSAID-treated GEP
NET
populations. In addition, 100 microM sulindac or indomethacin induced apoptosis. All 3 COX inhibitors prevented
CDK
-2 activation. In parallel to the NSAID-mediated reduction of
CDK
-2 activity, p21(cip-1) promoter activity and cellular p21(cip-1) levels increased and p21(cip-1) was sequestered into
CDK
-2 complexes. Thus, the G1 arrest likely resulted from p21(cip-1)-dependent inhibition of
CDK
-2 activity. At therapeutically relevant concentrations, sulindac significantly reduced GEP
NET
cell numbers, whereas IFN-alpha and octreotide remained ineffective. The extent of growth inhibition in GEP NETs was comparable to the antiproliferative effects of sulindac in established NSAID-sensitive cell models. NSAIDs acted as potent antiproliferative agents in GEP
NET
cells via G1 cell-cycle arrest and might therefore offer a therapeutic alternative to current treatment modalities.
...
PMID:Nonsteroidal anti-inflammatory drugs inhibit growth of human neuroendocrine tumor cells via G1 cell-cycle arrest. 1456 37
