Indomethacin as a Multi-target Anticancer Agent via Transmembrane Receptor-mediated Tumor Suppression: The Need for de novo Drug Derivatization.

INTRODUCTION: Besides COX-inhibitory activities, other mechanisms underlying indomethacin's potential as an anticancer agent are being explored, including those related to the mediation of prostaglandin signaling through transmembrane receptors in solid tumors. METHODS: In this mini-review, we summarize available information about modulation of transmembrane receptor signaling by indomethacin, including death receptors, EP receptors, receptor tyrosine kinases (RTKs), chemokine receptors, cannabinoid receptors, ACE2, P2X7, IP, and FZD/LRP5/6 receptors associated with Wnt pathways. RESULTS: The presented data indicate that indomethacin may inhibit PGE₂-induced EP signaling, affect EGFR/FGFR and CXCR3 signaling pathways, increase death receptor-mediated apoptosis, and influence various types of receptor cross-talk involved in proliferation, angiogenesis, immune evasion, invasion, and metastasis. However, the most consistent results were obtained in colorectal cancer cells, while the role of indomethacin in breast, ovarian, and prostate cancers appears to be more contextual and receptor-profile dependent. DISCUSSION: Overall, our review suggests that indomethacin functions mainly as a receptor signaling modulator rather than a selective receptor antagonist. The potential clinical application of indomethacin for cancer treatment is hindered by its poor selectivity towards COX enzymes, toxicity, and lack of specificity. CONCLUSION: Despite the possibility of using indomethacin as a template structure for creating more selective drugs, it seems that indomethacin cannot serve as a drug for anticancer therapy alone. This conclusion specifically positions parent indomethacin as a chemically modifiable scaffold for rational derivative development rather than as a final therapeutic endpoint.