BACKGROUND: The current study was undertaken to characterize the effect of 
anti-metabolites on inducing CXCL8 signaling and determining whether the 
constitutive and/or drug-induced CXCL8 signaling in metastatic prostate cancer 
(CaP) cells modulates their sensitivity to this class of agent.
METHODS: The response of metastatic CaP cells to 5-Fluorouracil (5-FU), 
Pemetrexed or Tomudex was determined using cell count assays, flow cytometry and 
PARP cleavage analysis. Quantitative-PCR, ELISA and immunoblots were employed to 
determine effects of drugs or CXCL8 administration on target gene/protein 
expression.
RESULTS: Administration of 5-FU but not pemetrexed potentiated CXCL8 secretion 
and increased CXCR1 and CXCR2 gene expression in metastatic PC3 cells. 
Consistent with this, the inhibition of CXCL8 signaling using a CXCR2 
antagonist, AZ10397767, increased the cytotoxicity of 5-FU by 4-fold (P<0.001), 
and increased 5-FU-induced apoptosis in PC3 cells (P<0.01). In contrast, while 
administration of AZ10397767 had no effect on the sensitivity of pemetrexed, the 
CXCR2 antagonist exerted the greatest effect in increasing the sensitivity of 
PC3 cells to Tomudex, a directed thymidylate synthase (TS) inhibitor. Subsequent 
experiments confirmed that administration of recombinant human CXCL8 increased 
TS expression, a response mediated in part by the CXCR2 receptor. Moreover, 
siRNA-mediated knockdown of the CXCL8-target gene Bcl-2 increased the 
sensitivity of PC3 cells to 5-FU.
CONCLUSIONS: CXCL8 signaling provides a selective resistance of metastatic 
prostate cancer cells to specific anti-metabolites by promoting a 
target-associated resistance, in addition to underpinning an evasion of 
treatment-induced apoptosis.