Introduction Advances in surgical resection, neo-adjuvant therapies and efforts to ensure early detection have led to a reduction in colorectal cancer mortality rates since the 1970s. Despite this, around 40% of patients die from recurrence or metastatic disease, making it the second most common cause of cancer related death in the UK. Poor response to adjuvant treatment for colorectal cancer continues to pose a significant problem.
Colorectal Cancer Stem Cells (CSC), are thought to be responsible for fuelling resistance and driving recurrent disease.1The identification of a reliable CSC marker, LGR5, 2has enabled further investigation and it has been demonstrated that both the function and survival of colorectal CSCs is driven by COX-2/PGE2and BCL-3/NFκB signalling pathways.3
Therefore, we aimed to determine whether Aspirin, through inhibiting PGE2production and BCL-3 expression, can enhance the response to radiotherapy, in colorectal cancer cells.
Method Colorectal carcinoma (HCA7/P, LS174T, LoVo) and adenoma (AN/C1, RG/C2) cell lines were treated with Aspirin, (1–2 mM, 24–96 h). Cell survival (cell yield and apoptosis) and protein expression (analysed by Western blotting), were determined. Colorectal cancer cells were seeded at low densities and treated with combinations of Aspirin and/or γ-radiation (Cs-137 source). Cell survival was determined by crystal violet cell viability assay.
Results 2 mM Aspirin decreased cell yield (e.g. LoVo- Control 26.7 × 106vs. 2 mM Aspirin 9.4 × 106, p = 0.002) and increased apoptosis (e.g. Lovo- Control 7.8 × 106vs. 2 mM Aspriin 19.5 × 106, p = 0.014) in carcinoma and adenoma cell lines at 72 and 96 h.
Western analysis showed Aspirin treatment reduced the expression of CSC related markers in both colorectal carcinoma and adenoma cell lines.
2mM Aspirin increased the sensitivity to 2.5Gy radiation in colorectal carcinoma cells, leading to an approximate two-fold decrease in cell survival, (e.g. HCA7/P- 2.5Gy radiation 81.9% survival vs. 43.4% for 2.5Gy and 2 mM Aspirin combined).
Suppression of BCL-3 expression, in addition to Aspirin, further enhanced response to radiation.
Conclusion Aspirin decreases cell survival and increases apoptosis in colorectal carcinoma and adenoma cell lines.
Furthermore, it enhances the response to radiation, reducing colorectal cancer cell survival. BCL-3 suppression may modulate this response.
Clinical translation, to further explore Aspirin’s role as a novel adjunct to radiation, is underway in our multi-centre prospective cohort study, (ASPIRE).
Disclosure of interest None Declared.
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