Abstract
Preoperative ketorolac, resolvins eliminated micrometastases, dormancy escape post-tumor resection.
Major Finding: Preoperative ketorolac, resolvins eliminated micrometastases, dormancy escape post-tumor resection.
Mechanism: COX1 inhibition is responsible for ketorolac's antitumor effects, and T-cell activity is required.
Impact: Potential of preoperative COX1 inhibitors or stimulation of inflammation should be further studied.
Chemotherapy, radiation, tumor resection, and even biopsy can cause inflammation that leads to dormancy escape or metastasis. Panigrahy and colleagues showed that in multiple mouse models, a dose of ketorolac or resolvins promoted elimination of lung micrometastases, helped prevent dormancy escape, and enhanced long-term survival after tumor resection. Additionally, ketorolac prevented post-chemotherapy dormancy escape in mice injected with cisplatin-, vincristine-, or 5-fluorouracil–stimulated cancer cells. Importantly, all these results held only when ketorolac was administered preoperatively, but not postoperatively, when anti-inflammatory drugs are typically prescribed. Ketorolac's protective effects appear dependent on inhibition of COX1, which is preferentially inhibited by ketorolac; preoperative treatment with other selective COX1 inhibitors or resolvins also improved long-term survival after tumor resection. LC-MS/MS profiling showed thromboxane B2 (TXB2), a hydration product of COX1-derived thromboxane A2 (TXA2), was reduced in ketorolac-treated mice compared with controls after tumor resection, implying TXA2 may be involved in ketorolac's effects. Further highlighting TXA2's role, thromboxane prostanoid (TP) receptor (which is activated by TXA2) KO mice had greater long-term survival than wild-type mice. Moreover, a TP-TXA2 antagonist prolonged survival following tumor resection, whereas a TP receptor agonist increased lung metastasis and reduced ketorolac's protective effects. Because the selective COX2 inhibitor celecoxib abolished ketorolac's life-span extension when the two drugs were coadministered before tumor resection, basal COX2 activity may also be important for ketorolac's effects and stimulation of inflammation resolution. Immune checkpoint blockade improved the antitumor activity of ketorolac, whereas athymic mice did not exhibit antitumor effects, indicating that T-cell activity is also required. Preoperative administration of resolvins, omega-3 fatty acid–derived immunoresolvent agonists, also exhibited antitumor activity, but an omega-3 fatty acid–rich diet combined with low-dose aspirin did not yield any long-term survivors. Combination of chemotherapy with anti-inflammatory or proresolution therapies may be useful as it unleashes T-cell immunity to help fight therapy-stimulated cancer. Further investigation on this treatment's potential to enhance the effectiveness of current cancer therapies and possibly prevent tumor recurrence may be fruitful.
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