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Circumvention of nuclear factor kappaB-induced chemoresistance by cytoplasmic-targeted anthracyclines.
- Source :
-
Molecular pharmacology [Mol Pharmacol] 2004 Apr; Vol. 65 (4), pp. 1038-47. - Publication Year :
- 2004
-
Abstract
- 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.
- Subjects :
- Animals
Ataxia Telangiectasia Mutated Proteins
Cell Cycle Proteins
Cell Line
Cytoplasm drug effects
Cytoplasm enzymology
DNA Damage
DNA-Binding Proteins
Doxorubicin analogs & derivatives
Doxorubicin pharmacology
Enzyme Activation
I-kappa B Kinase
Mice
Protein Kinase C-delta
Protein Serine-Threonine Kinases metabolism
Proto-Oncogene Proteins c-bcl-2 metabolism
Transfection
Tumor Suppressor Protein p53 metabolism
Tumor Suppressor Proteins
bcl-X Protein
Anthracyclines pharmacology
NF-kappa B metabolism
Protein Kinase C metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0026-895X
- Volume :
- 65
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Molecular pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 15044634
- Full Text :
- https://doi.org/10.1124/mol.65.4.1038