Induction of cell death by the CXCR2 antagonist SB225002 in colorectal cancer and stromal cells

Molecular targeted therapies have had great success in cancer treatment due to their high efficacy and selectivity. Identifying specific prognostic/predictive biomarkers helps clinicians stratify patients according to individual characteristics and improves patient quality of life in terms of disease control and survival. In our previous work, we identified Interleukin-8 as an important prognostic biomarker according to specific genomic alterations of colorectal cancers, leading us to investigate the effects of its axis inhibition, by targeting the Interleukin-8 receptors CXCR1 and CXCR2. Here, we show that dual CXCR1/2 inhibition does not affect colorectal cancer cell viability, whereas CXCR2-selective inhibition by SB225002 reduces cell viability in responder colorectal cancer cell lines. More specifically, these responder cells undergo programmed cell death upon SB225002 treatment, while non responder cell lines incur in a reversible G2/M arrest. Interestingly, the same response in terms of inhibition of cell viability also occurs in the stromal compartment (normal fibroblasts): however, in this compartment, the G2/M block is non reversible, hence leading to non-apoptotic cell death. These findings suggest that SB225002 could be a potential therapeutic agent in colorectal cancer, by affecting not only cell viability, but also tumor-stroma interactions.