Postoperative administration of ketorolac averts morphine-induced angiogenesis and metastasis in triple-negative breast cancer.

Opioids (i.e. morphine) were found to induce triple negative breast cancer (TNBC) metastasis while nonsteroidal anti-inflammatory drugs (i.e. ketolorac) were associated with decreased metastasis in TNBC. These contradictory findings demand clarification on the effect of postoperative morphine and ketorolac on TNBC metastasis.

TNBC xenograft mice were established using MDA-MB-231 cells. When tumors reached ~100 mm³, the primary tumor was resected. Mice were then randomly assigned to four groups (n = 14): (i) saline, (ii) morphine (10 mg kg^-1) (iii) morphine + ketorolac (10 mg kg^-1 of morphine and 20 mg kg^-1 of ketorolac) (iv) ketorolac (20 mg kg^-1); administrated for three consecutive days after resection. Three weeks after resection, the number of lung metastases was measured. Microvessel density, thrombospondin-1 (TSP-1) and c-Myc expression in recurrent tumors were determined. To elucidate the above phenomenon in vitro, MDA-MB-231 cells were treated according to the regiment above; with or without supplementation of an AKT inhibitor to determine the activation of PI3K/AKT/c-Myc pathway.

In mice, morphine promoted TNBC metastasis and angiogenesis, decreased TSP-1 expression and increased c-Myc expression, while co-administration of ketorolac significantly reversed the phenotypes above (p < .05). Mechanistically, morphine inhibited TSP-1 secretion by activating PI3K/AKT/c-Myc pathway (p < .05), while ketorolac promoted TSP-1 secretion (p < .05) by suppressing PI3K/AKT/c-Myc pathway.Our study indicated that morphine enhanced TNBC metastasis and angiogenesis while ketorolac suppressed this effect. Mechanistically, this may be related to the enhancement of TSP-1 synthesis after ketorolac administration which further de-activated PI3K/AKT/c-Myc pathway.