RT Journal Article
SR Electronic
T1 Circumvention of Nuclear Factor κB-Induced Chemoresistance by Cytoplasmic-Targeted Anthracyclines
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1038
OP 1047
DO 10.1124/mol.65.4.1038
VO 65
IS 4
A1 Jennifer D. Bilyeu
A1 Ganesh R. Panta
A1 Lakita G. Cavin
A1 Christina M. Barrett
A1 Eddie J. Turner
A1 Trevor W. Sweatman
A1 Mervyn Israel
A1 Leonard Lothstein
A1 Marcello Arsura
YR 2004
UL http://molpharm.aspetjournals.org/content/65/4/1038.abstract
AB Nuclear factor κB (NF-κB) 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-κB activation, in this report, we determined the mechanism of NF-κB 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-κB activity in response to drug treatment relies on the activation of PKC-δ and NF-κB-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-κB activation nor ectopic expression of Bcl-XL 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-κB.