TY - JOUR T1 - Circumvention of Nuclear Factor κB-Induced Chemoresistance by Cytoplasmic-Targeted Anthracyclines JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1038 LP - 1047 DO - 10.1124/mol.65.4.1038 VL - 65 IS - 4 AU - Jennifer D. Bilyeu AU - Ganesh R. Panta AU - Lakita G. Cavin AU - Christina M. Barrett AU - Eddie J. Turner AU - Trevor W. Sweatman AU - Mervyn Israel AU - Leonard Lothstein AU - Marcello Arsura Y1 - 2004/04/01 UR - http://molpharm.aspetjournals.org/content/65/4/1038.abstract N2 - 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. ER -