Enhancement of TPA-induced growth inhibition and apoptosis in myeloid leukemia cells by BAY 11-7082, an NF-kappaB inhibitor.
The phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA) is a potent stimulator of differentiation and apoptosis in myeloid leukemia cells. In the present study, we investigated the role of the transcription factor NF-kappaB in TPA-induced growth inhibition and apoptosis in the myeloid leukemia HL-60 cell line and its TPA-resistant cell variant HL-525. Unlike the parental cell line, HL-525 cells are protein kinase C (PKC)-beta deficient and resistant to TPA-induced differentiation and apoptosis. We found that treatment of HL-60 cells with TPA resulted in a concentration-dependent growth inhibition and an increase in apoptotic cells. TPA only had a small effect on growth and apoptosis in HL-525 cells. Treatment of HL-60 cells with TPA (0.64-3.2 nM) caused a rapid activation of NF-kappaB as determined by electrophoresis mobility shift assay (EMSA) and immunocytochemistry. Although the basal level of NF-kappaB activity was low in HL-60 cells, TPA-resistant HL-525 cells had a high basal level of NF-kappaB activity. Treatment of HL-525 cells with higher concentrations of TPA (16-80 nM) resulted in a further increase in NF-kappaB activity. (E)3-[(4-methylphenyl)-sulfonyl]-2-propenenitrile (BAY 11-7082; BAY), which inhibits IkappaB alpha phosphorylation and thus decreases NF-kappaB activation, was found to decrease TPA-induced nuclear translocation of NF-kappaB. Furthermore, BAY enhanced TPA-induced growth inhibition and apoptosis in both HL-60 and HL-525 cells. Results from the present study indicate that inhibition of NF-kappaB by BAY was associated with enhanced TPA-induced growth inhibition and apoptosis in human myeloid leukemia cells. TPA in combination with pharmacological inhibitors of NF-kappaB may improve the therapeutic efficacy of TPA and overcome the resistance to TPA in some myeloid leukemia patients.
Hansson
Annette
A
Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
Marín
Yarí E
YE
Suh
Junghan
J
Rabson
Arnold B
AB
Chen
Suzie
S
Huberman
Eliezer
E
Chang
Richard L
RL
Conney
Allan H
AH
Zheng
Xi
X
D021581:Active Transport, Cell Nucleus; D017209:Apoptosis; D002448:Cell Adhesion; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival; D004247:DNA / Q000737:chemistry; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D018922:HL-60 Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D016130:Immunophenotyping; D007951:Leukemia, Myeloid / Q000188:drug therapy*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology*; D010766:Phosphorylation; D011419:Propidium / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D064546:Protein Kinase C beta; D013450:Sulfones / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D013997:Time Factors
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D009570:Nitriles; D013450:Sulfones; D000072000:NF-KappaB Inhibitor alpha; D011419:Propidium; D004247:DNA; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D013755:Tetradecanoylphorbol Acetate