Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 510120 Guangzhou, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.
Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 510120 Guangzhou, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.
Life Sci. 2020 Jun 15;251:117604. doi: 10.1016/j.lfs.2020.117604. Epub 2020 Mar 31.
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 mm, the primary tumor was resected. Mice were then randomly assigned to four groups (n = 14): (i) saline, (ii) morphine (10 mg kg) (iii) morphine + ketorolac (10 mg kg of morphine and 20 mg kg of ketorolac) (iv) ketorolac (20 mg kg); 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.
阿片类药物（如吗啡）被发现可诱导三阴性乳腺癌（TNBC）转移，而非甾体抗炎药（如酮咯酸）则与 TNBC 转移减少相关。这些相互矛盾的发现需要澄清术后吗啡和酮咯酸对 TNBC 转移的影响。
使用 MDA-MB-231 细胞建立 TNBC 异种移植小鼠模型。当肿瘤达到~100mm 时，切除原发肿瘤。然后将小鼠随机分为四组（n=14）：（i）生理盐水，（ii）吗啡（10mg/kg），（iii）吗啡+酮咯酸（吗啡 10mg/kg 和酮咯酸 20mg/kg），（iv）酮咯酸（20mg/kg）；切除后连续 3 天给药。切除后 3 周，测量肺转移的数量。检测复发性肿瘤中的微血管密度、血小板反应蛋白-1（TSP-1）和 c-Myc 表达。为了在体外阐明上述现象，根据上述方案处理 MDA-MB-231 细胞；或不补充 AKT 抑制剂，以确定 PI3K/AKT/c-Myc 通路的激活情况。
在小鼠中，吗啡促进 TNBC 转移和血管生成，降低 TSP-1 表达，增加 c-Myc 表达，而酮咯酸的联合使用则显著逆转了上述表型（p<0.05）。在机制上，吗啡通过激活 PI3K/AKT/c-Myc 通路抑制 TSP-1 分泌（p<0.05），而酮咯酸通过抑制 PI3K/AKT/c-Myc 通路促进 TSP-1 分泌（p<0.05）。
本研究表明，吗啡增强了 TNBC 的转移和血管生成，而酮咯酸则抑制了这种作用。在机制上，这可能与酮咯酸给药后 TSP-1 合成增强有关，进一步使 PI3K/AKT/c-Myc 通路失活。
