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, Marcello Arsura

Research output: Contribution to journalArticle

17 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1038-1047
Number of pages10
JournalMolecular pharmacology
Volume65
Issue number4
DOIs
StatePublished - Apr 1 2004

Fingerprint

Anthracyclines
Protein Kinase C
Protein Isoforms
Phosphotransferases
Diglycerides
Phorbol Esters
Ataxia
DNA Damage
Phosphorylation
Pharmaceutical Preparations
N-benzyladriamycin-14-valerate

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

Bilyeu, J. D., Panta, G. R., Cavin, L. G., Barrett, C. M., Turner, E. J., Sweatman, T. W., ... Arsura, M. (2004). Circumvention of Nuclear Factor κB-Induced Chemoresistance by Cytoplasmic-Targeted Anthracyclines. Molecular pharmacology, 65(4), 1038-1047. https://doi.org/10.1124/mol.65.4.1038

Circumvention of Nuclear Factor κB-Induced Chemoresistance by Cytoplasmic-Targeted Anthracyclines. / Bilyeu, Jennifer D.; Panta, Ganesh R.; Cavin, Lakita G.; Barrett, Christina M.; Turner, Eddie J.; Sweatman, Trevor W.; Israel, Mervyn; Lothstein, Leonard; Arsura, Marcello.

In: Molecular pharmacology, Vol. 65, No. 4, 01.04.2004, p. 1038-1047.

Research output: Contribution to journalArticle

Bilyeu, JD, Panta, GR, Cavin, LG, Barrett, CM, Turner, EJ, Sweatman, TW, Israel, M, Lothstein, L & Arsura, M 2004, 'Circumvention of Nuclear Factor κB-Induced Chemoresistance by Cytoplasmic-Targeted Anthracyclines', Molecular pharmacology, vol. 65, no. 4, pp. 1038-1047. https://doi.org/10.1124/mol.65.4.1038
Bilyeu JD, Panta GR, Cavin LG, Barrett CM, Turner EJ, Sweatman TW et al. Circumvention of Nuclear Factor κB-Induced Chemoresistance by Cytoplasmic-Targeted Anthracyclines. Molecular pharmacology. 2004 Apr 1;65(4):1038-1047. https://doi.org/10.1124/mol.65.4.1038
Bilyeu, Jennifer D. ; Panta, Ganesh R. ; Cavin, Lakita G. ; Barrett, Christina M. ; Turner, Eddie J. ; Sweatman, Trevor W. ; Israel, Mervyn ; Lothstein, Leonard ; Arsura, Marcello. / Circumvention of Nuclear Factor κB-Induced Chemoresistance by Cytoplasmic-Targeted Anthracyclines. In: Molecular pharmacology. 2004 ; Vol. 65, No. 4. pp. 1038-1047.
@article{29262dd429db43ec88bde03655af19d6,
title = "Circumvention of Nuclear Factor κB-Induced Chemoresistance by Cytoplasmic-Targeted Anthracyclines",
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.",
author = "Bilyeu, {Jennifer D.} and Panta, {Ganesh R.} and Cavin, {Lakita G.} and Barrett, {Christina M.} and Turner, {Eddie J.} and Sweatman, {Trevor W.} and Mervyn Israel and Leonard Lothstein and Marcello Arsura",
year = "2004",
month = "4",
day = "1",
doi = "10.1124/mol.65.4.1038",
language = "English (US)",
volume = "65",
pages = "1038--1047",
journal = "Molecular Pharmacology",
issn = "0026-895X",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "4",

}

TY - JOUR

T1 - Circumvention of Nuclear Factor κB-Induced Chemoresistance by Cytoplasmic-Targeted Anthracyclines

AU - Bilyeu, Jennifer D.

AU - Panta, Ganesh R.

AU - Cavin, Lakita G.

AU - Barrett, Christina M.

AU - Turner, Eddie J.

AU - Sweatman, Trevor W.

AU - Israel, Mervyn

AU - Lothstein, Leonard

AU - Arsura, Marcello

PY - 2004/4/1

Y1 - 2004/4/1

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.

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.

UR - http://www.scopus.com/inward/record.url?scp=1842532926&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=1842532926&partnerID=8YFLogxK

U2 - 10.1124/mol.65.4.1038

DO - 10.1124/mol.65.4.1038

M3 - Article

C2 - 15044634

AN - SCOPUS:1842532926

VL - 65

SP - 1038

EP - 1047

JO - Molecular Pharmacology

JF - Molecular Pharmacology

SN - 0026-895X

IS - 4

ER -