Constitutive activation of nuclear factor (NF)-kappaB is linked with the 
intrinsic resistance of androgen-independent prostate cancer (AIPC) to cytotoxic 
chemotherapy. Interleukin-8 (CXCL8) is a transcriptional target of NF-kappaB 
whose expression is elevated in AIPC. This study sought to determine the 
significance of CXCL8 signaling in regulating the response of AIPC cells to 
oxaliplatin, a drug whose activity is reportedly sensitive to NF-kappaB 
activity. Administration of oxaliplatin to PC3 and DU145 cells increased 
NF-kappaB activity, promoting antiapoptotic gene transcription. In addition, 
oxaliplatin increased the transcription and secretion of CXCL8 and the related 
CXC-chemokine CXCL1 and increased the transcription and expression of 
CXC-chemokine receptors, especially CXC-chemokine receptor (CXCR) 2, which 
transduces the biological effects of CXCL8 and CXCL1. Stimulation of AIPC cells 
with CXCL8 potentiated NF-kappaB activation in AIPC cells, increasing the 
transcription and expression of NF-kappaB-regulated antiapoptotic genes of the 
Bcl-2 and IAP families. Coadministration of a CXCR2-selective antagonist, 
AZ10397767 (Bioorg Med Chem Lett 18:798-803, 2008), attenuated 
oxaliplatin-induced NF-kappaB activation, increased oxaliplatin cytotoxicity, 
and potentiated oxaliplatin-induced apoptosis in AIPC cells. Pharmacological 
inhibition of NF-kappaBorRNA interference-mediated suppression of Bcl-2 and 
survivin was also shown to sensitize AIPC cells to oxaliplatin. Our results 
further support NF-kappaB activity as an important determinant of cancer cell 
sensitivity to oxaliplatin and identify the induction of autocrine CXCR2 
signaling as a novel mode of resistance to this drug.