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Research ArticleArticle

Circumvention of Nuclear Factor κB-Induced Chemoresistance by Cytoplasmic-Targeted Anthracyclines

Jennifer D. Bilyeu, Ganesh R. Panta, Lakita G. Cavin, Christina M. Barrett, Eddie J. Turner, Trevor W. Sweatman, Mervyn Israel, Leonard Lothstein and Marcello Arsura
Molecular Pharmacology April 2004, 65 (4) 1038-1047; DOI: https://doi.org/10.1124/mol.65.4.1038
Jennifer D. Bilyeu
Department of Pharmacology, Center for Anticancer Drug Research, University of Tennessee Cancer Institute, University of Tennessee College of Medicine, Memphis, Tennessee
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Ganesh R. Panta
Department of Pharmacology, Center for Anticancer Drug Research, University of Tennessee Cancer Institute, University of Tennessee College of Medicine, Memphis, Tennessee
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Lakita G. Cavin
Department of Pharmacology, Center for Anticancer Drug Research, University of Tennessee Cancer Institute, University of Tennessee College of Medicine, Memphis, Tennessee
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Christina M. Barrett
Department of Pharmacology, Center for Anticancer Drug Research, University of Tennessee Cancer Institute, University of Tennessee College of Medicine, Memphis, Tennessee
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Eddie J. Turner
Department of Pharmacology, Center for Anticancer Drug Research, University of Tennessee Cancer Institute, University of Tennessee College of Medicine, Memphis, Tennessee
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Trevor W. Sweatman
Department of Pharmacology, Center for Anticancer Drug Research, University of Tennessee Cancer Institute, University of Tennessee College of Medicine, Memphis, Tennessee
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Mervyn Israel
Department of Pharmacology, Center for Anticancer Drug Research, University of Tennessee Cancer Institute, University of Tennessee College of Medicine, Memphis, Tennessee
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Leonard Lothstein
Department of Pharmacology, Center for Anticancer Drug Research, University of Tennessee Cancer Institute, University of Tennessee College of Medicine, Memphis, Tennessee
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Marcello Arsura
Department of Pharmacology, Center for Anticancer Drug Research, University of Tennessee Cancer Institute, University of Tennessee College of Medicine, Memphis, Tennessee
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Abstract

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.

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Molecular Pharmacology: 65 (4)
Molecular Pharmacology
Vol. 65, Issue 4
1 Apr 2004
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Research ArticleArticle

Circumvention of Nuclear Factor κB-Induced Chemoresistance by Cytoplasmic-Targeted Anthracyclines

Jennifer D. Bilyeu, Ganesh R. Panta, Lakita G. Cavin, Christina M. Barrett, Eddie J. Turner, Trevor W. Sweatman, Mervyn Israel, Leonard Lothstein and Marcello Arsura
Molecular Pharmacology April 1, 2004, 65 (4) 1038-1047; DOI: https://doi.org/10.1124/mol.65.4.1038

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Research ArticleArticle

Circumvention of Nuclear Factor κB-Induced Chemoresistance by Cytoplasmic-Targeted Anthracyclines

Jennifer D. Bilyeu, Ganesh R. Panta, Lakita G. Cavin, Christina M. Barrett, Eddie J. Turner, Trevor W. Sweatman, Mervyn Israel, Leonard Lothstein and Marcello Arsura
Molecular Pharmacology April 1, 2004, 65 (4) 1038-1047; DOI: https://doi.org/10.1124/mol.65.4.1038
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