Selective cyclooxygenase 2 inhibitor NS-398 induces apoptosis in myeloma cells via a Bcl-2 independent pathway.
NS-398, a selective inhibitor of cyclooxygenase 2 (COX-2), has been reported to inhibit growth and induce apoptosis in several cancer cell lines that overexpress COX-2. However it has not been extensively studied in multiple myeloma (MM). Here, we studied the effects of COX-2 inhibitors on MM cell lines and primary myeloma patient cells. We investigated the effects of NS-398 on proliferation and apoptosis in three myeloma cell lines (PCM6, U266 and RPMI8226) and isolated CD138-positive cells from MM patients. Furthermore, the combined effects of NS-398 plus dexamethasone (Dex) or thalidomide (Thal) were investigated. All myeloma cell lines express COX-2. NS-398 inhibited growth and induced apoptosis in PCM6, RPMI8226 and CD138-positive MM cells in a time- and dose-dependent manner. At low concentrations (10 microM), NS-398 primarily induced growth arrest without affecting cell viability, but at higher concentrations (over 25 microM), apoptosis was induced. During the process of apoptosis, the number of Fas-positive cells increased. Downstream signals of Fas, such as caspase 8, 3 and 9, were also activated. On the other hand, protein levels of the Bcl-2 family did not change, although mitochondrial transmembrane potential ((Delta)(psi)m) was decreased. Combined incubation with Dex or Thal enhanced NS-398-induced growth inhibition and apoptosis in RPMI8226 cells. The combined effect of Dex was more potent than that of Thal. Our findings suggests that COX-2 plays an important role in regulation of apoptosis in myeloma cells, and COX-2 inhibitors might serve as an effective tool for future chemoprevention and/or treatment of myeloma.
Zhang
Min
M
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Abe
Yasunobu
Y
Matsushima
Takamitsu
T
Nishimura
Junji
J
Nawata
Hajime
H
Muta
Koichiro
K
D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D053222:Fas Ligand Protein; D019254:Genes, bcl-2 / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000502:physiology; D008565:Membrane Proteins; D009101:Multiple Myeloma / Q000201:enzymology / Q000378:metabolism; D009578:Nitrobenzenes / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology*; D013792:Thalidomide / Q000494:pharmacology
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D013792:Thalidomide; D003907:Dexamethasone; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D020169:Caspases