Anwulignan Alleviates Bone Cancer Pain by Modulating the PPARα/CXCR2 Signaling Pathway in the Rat Spinal Cord

Overview

Journal CNS Neurosci Ther

Specialties Neurology
Pharmacology

Date 2025 Mar 13

PMID 40079428

Authors

Yueliang Wang

Qingying Liu

Yingying Jiang

Longfei Mao

Mohamed Zoubaa

Jian Wang

Huilian Bu

Minyu Ma

Jingjing Yuan

Jing Cao

Xiaochong Fan

Affiliations

Soon will be listed here.

Abstract

Aims: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

References

van den Beuken-van Everdingen M, Hochstenbach L, Joosten E, Tjan-Heijnen V, Janssen D . Update on Prevalence of Pain in Patients With Cancer: Systematic Review and Meta-Analysis. J Pain Symptom Manage. 2016; 51(6):1070-1090.e9. DOI: 10.1016/j.jpainsymman.2015.12.340. View

Che N, Li M, Liu X, Cui C, Gong J, Xuan Y . Macelignan prevents colorectal cancer metastasis by inhibiting M2 macrophage polarization. Phytomedicine. 2023; 122:155144. DOI: 10.1016/j.phymed.2023.155144. View

Lazennec G, Richmond A . Chemokines and chemokine receptors: new insights into cancer-related inflammation. Trends Mol Med. 2010; 16(3):133-44. PMC: 2840699. DOI: 10.1016/j.molmed.2010.01.003. View

Zhang X, Su Q, Zhang Y, Rong R, Chen S, He L . A promising natural product in diffuse large B-cell lymphoma therapy by targeting PIM1. Ann Hematol. 2024; 103(8):2905-2915. DOI: 10.1007/s00277-024-05670-7. View

Zhang Y, Sang R, Bao J, Jiang Z, Qian D, Zhou Y . Schwann cell-derived CXCL2 contributes to cancer pain by modulating macrophage infiltration in a mouse breast cancer model. Brain Behav Immun. 2023; 109:308-320. DOI: 10.1016/j.bbi.2023.02.004. View

Caillaud M, Patel N, White A, Wood M, Contreras K, Toma W . Targeting Peroxisome Proliferator-Activated Receptor-α (PPAR- α) to reduce paclitaxel-induced peripheral neuropathy. Brain Behav Immun. 2021; 93:172-185. PMC: 8226373. DOI: 10.1016/j.bbi.2021.01.004. View

Anggakusuma , Yanti , Hwang J . Effects of macelignan isolated from Myristica fragrans Houtt. on UVB-induced matrix metalloproteinase-9 and cyclooxygenase-2 in HaCaT cells. J Dermatol Sci. 2009; 57(2):114-22. DOI: 10.1016/j.jdermsci.2009.10.005. View

Hargreaves K, Dubner R, Brown F, Flores C, Joris J . A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain. 1988; 32(1):77-88. DOI: 10.1016/0304-3959(88)90026-7. View

Moehring F, Halder P, Seal R, Stucky C . Uncovering the Cells and Circuits of Touch in Normal and Pathological Settings. Neuron. 2018; 100(2):349-360. PMC: 6708582. DOI: 10.1016/j.neuron.2018.10.019. View

10.

Wang X, Lin C, Jin S, Wang Y, Peng Y, Wang X . Cannabidiol alleviates neuroinflammation and attenuates neuropathic pain via targeting FKBP5. Brain Behav Immun. 2023; 111:365-375. DOI: 10.1016/j.bbi.2023.05.008. View

11.

Zheng X, Wu Y, Huang J, Wu A . Neurophysiological mechanisms of cancer-induced bone pain. J Adv Res. 2022; 35:117-127. PMC: 8721251. DOI: 10.1016/j.jare.2021.06.006. View

12.

Martyn J, Mao J, Bittner E . Opioid Tolerance in Critical Illness. N Engl J Med. 2019; 380(4):365-378. PMC: 6897318. DOI: 10.1056/NEJMra1800222. View

13.

Zou Y, Zhan T, Liu J, Tan J, Liu W, Huang S . CXCL6 promotes the progression of NAFLD through regulation of PPARα. Cytokine. 2023; 174:156459. DOI: 10.1016/j.cyto.2023.156459. View

14.

SenGupta S, Subramanian B, Parent C . Getting TANned: How the tumor microenvironment drives neutrophil recruitment. J Leukoc Biol. 2018; 105(3):449-462. PMC: 8193910. DOI: 10.1002/JLB.3RI0718-282R. View

15.

Wang J, Zhang Q, Zhao L, Li D, Fu Z, Liang L . Down-regulation of PPARα in the spinal cord contributes to augmented peripheral inflammation and inflammatory hyperalgesia in diet-induced obese rats. Neuroscience. 2014; 278:165-78. DOI: 10.1016/j.neuroscience.2014.07.071. View

16.

Wang Q, Wang J, Yu D, Zhang Q, Hu H, Xu M . Benzosceptrin C induces lysosomal degradation of PD-L1 and promotes antitumor immunity by targeting DHHC3. Cell Rep Med. 2024; 5(2):101357. PMC: 10897506. DOI: 10.1016/j.xcrm.2023.101357. View

17.

Ha H, Debnath B, Neamati N . Role of the CXCL8-CXCR1/2 Axis in Cancer and Inflammatory Diseases. Theranostics. 2017; 7(6):1543-1588. PMC: 5436513. DOI: 10.7150/thno.15625. View

18.

Scarborough B, Smith C . Optimal pain management for patients with cancer in the modern era. CA Cancer J Clin. 2018; 68(3):182-196. PMC: 5980731. DOI: 10.3322/caac.21453. View

19.

Donnelly C, Jiang C, Andriessen A, Wang K, Wang Z, Ding H . STING controls nociception via type I interferon signalling in sensory neurons. Nature. 2021; 591(7849):275-280. PMC: 7977781. DOI: 10.1038/s41586-020-03151-1. View

20.

Cheng Y, Ma X, Wei Y, Wei X . Potential roles and targeted therapy of the CXCLs/CXCR2 axis in cancer and inflammatory diseases. Biochim Biophys Acta Rev Cancer. 2019; 1871(2):289-312. DOI: 10.1016/j.bbcan.2019.01.005. View