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

Department of Pharmacology, Center for Anticancer Drug Research, University of Tennessee Cancer Institute, University of Tennessee College of Medicine, Memphis, Tennessee

Nuclear factor B (NF-B) 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-B activation, in this report, we determined the mechanism of NF-B 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-B activity in response to drug treatment relies on the activation of PKC- and NF-B-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-B 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-B.

Received July 24, 2003; accepted December 23, 2003.

Address correspondence to: Marcello Arsura, Ph.D., University of Tennessee Cancer Institute (UTCI), Department of Pharmacology, College of Medicine, University of Tennessee Health Science Center, Crowe Building 401, 874 Union Avenue, Memphis, TN 38163. E-mail: marsura{at}utmem.edu.

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