Abstract
BackgroundThe 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.MethodsThe 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.ResultsAdministration 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.ConclusionsCXCL8 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.
Highlights
Treatment of advanced castrate-resistant metastatic prostate cancer (CRPC) remains a significant clinical unmet need
We have shown that stress-induced CXCL8 signaling attenuates the sensitivity of prostate cancer cells to undergo apoptosis in response to DNA-damaging agents [9,10], Hsp90directed inhibitors [15], death receptor agonists (TRAIL) [11] and androgen receptor (AR)-targeted therapeutics such as bicalutimide (Casodex) [13]
The emergence of a new generation of androgen signaling pathway inhibitors for use in CRPC patients will contribute to improved outcomes for many patients, it is clear that a more informed use of conventional chemotherapy agents will be necessary to improve clinical outcomes for patients for whom these new drugs fail to work. 5FU and its oral analog capecitabine have been reported to be safe as a second-line treatment for metastatic castrate-resistant CaP, with modest responses observed when administered in combination with docetaxel or oxaliplatin in small phase II trials [5,6]
Summary
Treatment of advanced castrate-resistant metastatic prostate cancer (CRPC) remains a significant clinical unmet need. The recent approval of abiraterone-acetate as a second-line treatment in CRPC is a major advance, this agent which targets the androgen synthesis pathway provides only a limited improvement in overall survival and only patients with a good performance status benefit from its provision [1,2]. Many tumours will be resistant to abiraterone in second-line treatment This mandates that efforts to expand the armoury of agents available to clinicians treating CRPC is not relaxed. Such efforts should not be restricted solely to the discovery of new agents but should exploit our continuing knowledge of the disease biology to define mechanisms of resistance and identify novel agents which can be exploited to improve the efficacy of existing chemotherapy agents. 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
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