Effects of nuclear factor-kappaB inhibitors and its implication on natural killer T-cell lymphoma cells.
Natural killer/T-cell lymphoma (NKTL) is a highly aggressive disease. Despite the use of various treatment regimens, the prognosis of NKTL is poor, and new treatment strategies need to be determined. Because of the significant survival potential, nuclear factor (NF)-kappaB has become one of the major targets for drug development. In this study, we explored the effect and action mechanism of NF-kappaB inhibitors, BAY 11-7082 and curcumin, on NKTL cell lines (NKL, NK-92 and HANK1). Electrophoretic mobility shift assay showed that NF-kappaB was constitutively active in HANK1, a chemoresistant cell line. BAY 11-7082 and curcumin suppressed NF-kappaB activation in a time- and dose-dependent manner, which finally resulted in cell death. BAY 11-7082- and curcumin-induced cell death was associated with downregulation of Bcl-xL, cyclin D1, XIAP and c-FLIP, followed by caspase-8, poly(ADP-ribose) polymerase cleavage and activation. Given that the chemoresistant NK-92 cells respond to NF-kappaB inhibitors but not to conventional drugs, BAY 11-7082 and curcumin could be potentially useful for achieving improved outcome in chemotherapy-refractory NKTL.
Kim
Kihyun
K
Department of Medicine, Sungkyunkwan University School of Medicine, Seoul, Korea. kkim@smc.samsung.co.kr
Ryu
Kyoungju
K
Ko
Younghyeh
Y
Park
Chaehwa
C
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D003474:Curcumin / Q000494:pharmacology*; D019938:Cyclin D1 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D024202:Electrophoretic Mobility Shift Assay; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects*; D016399:Lymphoma, T-Cell / Q000188:drug therapy* / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology*; D013997:Time Factors; D051636:X-Linked Inhibitor of Apoptosis Protein; D051020:bcl-X Protein
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; C494811:BCL2L1 protein, human; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D009570:Nitriles; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013450:Sulfones; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D051020:bcl-X Protein; D019938:Cyclin D1; D011065:Poly(ADP-ribose) Polymerases; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases; D003474:Curcumin