Circumvention of nuclear factor kappaB-induced chemoresistance by cytoplasmic-targeted anthracyclines.
Nuclear factor kappaB (NF-kappaB) has been implicated in inducible chemoresistance against anthracyclines. In an effort to improve the cytotoxicity of anthracyclines while reducing their cardiotoxic effects, we have developed a novel class of extranuclear-localizing 14-O-acylanthracyclines that bind to the phorbol ester/diacylglycerol-binding C1b domain of conventional and novel protein kinase C (PKC) isoforms, thereby promoting an apoptotic response. Because PKCs have been shown to be involved in NF-kappaB activation, in this report, we determined the mechanism of NF-kappaB activation by N-benzyladriamycin-14-valerate (AD 198) and N-benzyladriamycin-14-pivalate (AD 445), two novel 14-O-acylanthracylines. We show that the induction of NF-kappaB activity in response to drug treatment relies on the activation of PKC-delta and NF-kappaB-activating kinase (NAK), independent of ataxia telengectasia mutated and p53 activities. In turn, NAK activates the IKK complex through phosphorylation of the IKK-2 subunit. We find that neither NF-kappaB activation nor ectopic expression of Bcl-X(L) confers protection from AD 198-induced cell killing. Overall, our data indicate that activation of novel PKC isoforms by cytoplasmic-targeted 14-O-acylanthracyclines promotes an apoptotic response independent of DNA damage, which is unimpeded by inducible activation of NF-kappaB.
Bilyeu
Jennifer D
JD
Department of Pharmacology, Center for Anticancer Drug Research, University of Tennessee Cancer Institute, University of Tennessee College of Medicine, Memphis, Tennessee 38163, USA.
Panta
Ganesh R
GR
Cavin
Lakita G
LG
Barrett
Christina M
CM
Turner
Eddie J
EJ
Sweatman
Trevor W
TW
Israel
Mervyn
M
Lothstein
Leonard
L
Arsura
Marcello
M
D000818:Animals; D018943:Anthracyclines / Q000494:pharmacology*; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D002460:Cell Line; D003593:Cytoplasm / Q000187:drug effects / Q000201:enzymology; D004249:DNA Damage; D004268:DNA-Binding Proteins; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000494:pharmacology; D004789:Enzyme Activation; D051550:I-kappa B Kinase; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D051745:Protein Kinase C-delta; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins; D051020:bcl-X Protein
D018943:Anthracyclines; C494812:Bcl2l1 protein, mouse; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D051020:bcl-X Protein; D004317:Doxorubicin; C046808:N-benzyladriamycin-14-valerate; C497259:Prkcd protein, mouse; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse; D011493:Protein Kinase C; D051745:Protein Kinase C-delta