2. Academic Validation
  3. Blockers of Wnt3a, Wnt10a, or β-Catenin Prevent Chemotherapy-Induced Neuropathic Pain In Vivo

Blockers of Wnt3a, Wnt10a, or β-Catenin Prevent Chemotherapy-Induced Neuropathic Pain In Vivo

  • Neurotherapeutics. 2021 Jan;18(1):601-614. doi: 10.1007/s13311-020-00956-w.
Hee Kee Kim  # 1,  Jingi Bae  # 2,  Sung Ho Lee 3 4 5,  Seon-Hee Hwang 6,  Min-Sik Kim 7,  Moon Jong Kim 3 4 5,  Sohee Jun 3 4 5,  Chris L Cervantes 3 4 5,  Youn-Sang Jung 3 4 5,  Seunghoon Back 2,  Hangyeore Lee 2,  Seung-Eun Lee 8,  Patrick M Dougherty 6,  Sang-Won Lee 2,  Jae-Il Park 3 4 5,  Salahadin Abdi 6
Affiliations

Affiliations

  • 1 Department of Pain Medicine, Division of Anesthesiology, Critical Care & Pain Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. hkim9@mdanderson.org.
  • 2 Department of Chemistry, Center for Proteogenome Research, Korea University, Seoul, 02841, Republic of Korea.
  • 3 Department of Experimental Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
  • 4 Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
  • 5 Program in Genetics and Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
  • 6 Department of Pain Medicine, Division of Anesthesiology, Critical Care & Pain Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
  • 7 Department of New Biology, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, 42988, Republic of Korea.
  • 8 Department of Biomedical Science and Technology, Kyung Hee Medical Science Research Institute, Kyung Hee University, Seoul, 02447, Republic of Korea.
  • # Contributed equally.
PMID: 33128175 DOI: 10.1007/s13311-020-00956-w
Abstract

Although chemotherapy is a key Cancer treatment, many chemotherapeutic drugs produce chronic neuropathic pain, called chemotherapy-induced neuropathic pain (CINP), which is a dose-limiting adverse effect. To date, there is no medicine that prevents CINP in Cancer patients and survivors. We determined whether blockers of the canonical Wnt signaling pathway prevent CINP. Neuropathic pain was induced by intraperitoneal injection of paclitaxel (PAC) on four alternate days in male Sprague-Dawley rats or male Axin2-LacZ knock-in mice. XAV-939, LGK-974, and iCRT14, Wnt/β-catenin blockers, were administered intraperitoneally as a single or multiple doses before or after injury. Mechanical allodynia, phosphoproteome profiling, Wnt ligands, and inflammatory mediators were measured by von Frey filament, phosphoproteomics, reverse transcription-polymerase chain reaction, and Western blot analysis. Localization of β-catenin was determined by immunohistochemical analysis in the dorsal root ganglia (DRGs) in rats and human. Our phosphoproteome profiling of CINP rats revealed significant phosphorylation changes in Wnt signaling components. Importantly, repeated systemic injections of XAV-939 or LGK-974 prevented the development of CINP in rats. In addition, XAV-939, LGK-974, and iCRT14 ameliorated CINP. PAC increased Wnt3a and Wnt10a, activated β-catenin in DRG, and increased monocyte chemoattractant protein-1 and interleukin-1β in DRG. PAC also upregulated rAxin2 in mice. Furthermore, β-catenin was expressed in neurons, including Calcitonin gene-related protein-expressing neurons and satellite cells in rat and human DRG. In conclusion, chemotherapy increases Wnt3a, Wnt10a, and β-catenin in DRG and their pharmacological blockers prevent and ameliorate CINP, suggesting a target for the prevention and treatment of CINP.

Keywords

Chemotherapy-induced neuropathic pain, Wnt ligand, Wnt3a, Wnt10a, β-catenin, prevention.

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