Wang Yueliang, Liu Qingying, Jiang Yingying, Mao Longfei, Zoubaa Mohamed, Wang Jian, Bu Huilian, Ma Minyu, Yuan Jingjing, Cao Jing, Fan Xiaochong
Department of Pain Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
Department of Neuropharmacology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.
CNS Neurosci Ther. 2025 Mar;31(3):e70302. doi: 10.1111/cns.70302.
Advanced cancer patients frequently endure severe pain from bone metastases, and few effective treatments for bone cancer pain (BCP) exist. Although Anwulignan is known for its antioxidant, anti-inflammatory, and antitumor properties, its effects on BCP remain unclear. This study aims to explore the analgesic effects and mechanisms of Anwulignan on bone cancer pain.
Western blotting and immunofluorescence assessed molecular expression and localization. X-ray, micro-CT, TRAP, and ALP staining examined bone destruction in rats. MTT, colony formation assays, and in vivo imaging analyzed tumor changes. RNA-Seq identified differentially expressed genes, validated by ChIP analysis.
Here, we showed that Anwulignan alleviated mechanical, thermal, and cold hypersensitivity and spontaneous pain, prevented bone destruction, and suppressed local tumor growth in rats with BCP. Furthermore, Anwulignan was firmly bound to proliferator-activated receptor alpha (PPARα), increasing its thermal stability. Intrathecal (i.t.) injection of PPARα siRNA increased pain sensitivity in naive rats, and PPARα siRNA abrogated the analgesic effect of Anwulignan in BCP model rats. Moreover, the PPARα agonist pirinixic acid reduced BCP hypersensitivity and abrogated the upregulation of CXC chemokine receptor 2 (CXCR2). Importantly, PPARα bound to the CXCR2 promoter region, and Anwulignan could reverse the reduced binding of PPARα to CXCR2 caused by BCP.
Taken together, these results indicate that Anwulignan is a potential antitumor and analgesic agent that exerts its effects via upregulation of PPARα expression to inhibit the expression of CXCR2 and could be used for treating BCP.
晚期癌症患者常因骨转移而忍受剧痛，而针对骨癌痛（BCP）的有效治疗方法很少。尽管茴芹内酯以其抗氧化、抗炎和抗肿瘤特性而闻名，但其对BCP的影响仍不清楚。本研究旨在探讨茴芹内酯对骨癌痛的镇痛作用及其机制。
采用蛋白质免疫印迹法和免疫荧光法评估分子表达和定位。通过X射线、显微CT、抗酒石酸酸性磷酸酶（TRAP）和碱性磷酸酶（ALP）染色检测大鼠的骨质破坏情况。采用MTT法、集落形成试验和体内成像分析肿瘤变化。通过RNA测序鉴定差异表达基因，并通过染色质免疫沉淀分析进行验证。
在此，我们表明茴芹内酯可减轻BCP大鼠的机械性、热性和冷敏性以及自发性疼痛，预防骨质破坏，并抑制局部肿瘤生长。此外，茴芹内酯与过氧化物酶体增殖物激活受体α（PPARα）紧密结合，提高了其热稳定性。鞘内注射PPARα小干扰RNA（siRNA）可增加正常大鼠的疼痛敏感性，且PPARα siRNA可消除茴芹内酯对BCP模型大鼠的镇痛作用。此外，PPARα激动剂匹立尼酸可降低BCP的超敏反应，并消除CXC趋化因子受体2（CXCR2）的上调。重要的是，PPARα与CXCR2启动子区域结合，而茴芹内酯可逆转BCP导致的PPARα与CXCR2结合减少。
综上所述，这些结果表明茴芹内酯是一种潜在的抗肿瘤和镇痛剂，其通过上调PPARα表达来抑制CXCR2表达而发挥作用，可用于治疗BCP。
