Control of Lung Cancer with Aspirin‐Triggered Stimulation of Resolution

Background Inflammation in the tumor microenvironment is now recognized as a promoter of tumor growth. While substantial epidemiological evidence suggests that the anti‐inflammatory drug aspirin reduces cancer risk, the underlying mechanism remains unclear and toxicity has limited its clinical use. Aspirin increases resolvins ('aspirin‐triggered' resolvins (AT‐Rvs)) in humans, providing a novel pathway to explain the anti‐cancer activity of aspirin. We hypothesize that AT‐Rvs may partially account for the chemopreventive activity of aspirin in lung cancer via novel anti‐inflammatory and pro‐resolution mechanisms. Results Flow cytometry confirmed apoptotic/necrotic lung tumor cell debris by cytotoxic chemotherapeutic agents etoposide, cisplatin or with the targeted therapy erlotinib (Tarceva). Cisplatin‐induced Lewis lung carcinoma (LLC) debris stimulated tumor growth in mice in a dose‐dependent manner. AT‐Rvs enhance macrophage phagocytosis of lung tumor cell debris at nanomolar concentrations. To determine whether resolvins could inhibit spontaneous metastasis, we used a well‐established model in which resection of LLC stimulates spontaneous lung metastasis. Resolvins potently inhibited lung metastases and lung weight compared to vehicle‐treated mice. Conclusions Aspirin triggers the human body's production of resolvins. AT‐Rvs may provide a novel pathway and molecular mechanism to explain how aspirin reduces cancer risk so broadly. Research Support: RO1 01CA170549