Investigating the effects of aspirin in high-grade serous ovarian carcinoma models in vitro
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Aspirin is a non-steroidal anti-inflammatory drug. It blocks prostaglandin (PG) production by inhibiting cyclooxygenase 1 (COX-1) and COX-2 activity. There is now significant evidence about the therapeutic cancer-preventative effects of aspirin, especially as inflammation is a critical hallmark of tumour progression. Nevertheless, most studies investigating the anti-cancer effects of aspirin are on colorectal cancer. There is limited research in high-grade serous ovarian carcinoma (HGSOC), even though the inflammatory ovarian tumour microenvironment (TME) is important in promoting HGSOC progression. Aspirin treatment (≤7 days) did not inhibit the growth of two HGSOC cell lines, three colorectal cancer (CRC) cell lines, primary omental fibroblasts, and primary omental mesothelial cells. To ensure I was using preparing the drug correctly, I performed a prostanoid profile in aspirin-treated malignant cells. Aspirin reduced PG levels in malignant cells, primary omental fibroblasts, and mesothelial cells, but only when they were cultured in serum-free medium. Aspirin did not inhibit malignant or normal cell growth even in serum-free medium. I then investigated the actions of aspirin in multi-cellular models (four cell types) of HGSOC omental metastases. Treating multi-cellular models with aspirin in serum- free medium did not alter cell viability. However, performing a cytokine analysis showed that aspirin significantly and specifically reduced IL-8 secretion in multi- cellular models of HGSOC, monocultures of primary omental fibroblasts and mesothelial cells, but not monocultures of malignant cells. There was no action of aspirin on another 10 cytokines (including IL-6) that I measured. Results from monocultures of primary omental fibroblasts and mesothelial cells suggest that aspirin may reduce IL-8 release via COX-2-PGE2-EP2/EP4 pathway. Aspirin inhibition of IL-8 production by stromal cells in the TME via the COX-2-PGE2-EP2/EP4 pathway could potentially contribute to its cancer-preventive actions.
Authors
Lakshmi Varahan, BCollections
- Theoretical Physics [186]