Decitabine attenuates nociceptive behavior in a murine model of bone cancer pain

Camilla Kristine Appel, Nicole Newell Scheff, Chi Tonglien Viet, Brian Lee Schmidt, Anne Marie Heegaard

Research output: Contribution to journalArticle

Abstract

Bone cancer metastasis is extremely painful and decreases the quality of life of the affected patients. Available pharmacological treatments are not able to sufficiently ameliorate the pain, and as patients with cancer are living longer, new treatments for pain management are needed. Decitabine (5-aza-2′-deoxycytidine), a DNA methyltransferases inhibitor, has analgesic properties in preclinical models of postsurgical and soft-tissue oral cancer pain by inducing an upregulation of endogenous opioids. In this study, we report that daily treatment with decitabine (2 μg/g, intraperitoneally) attenuated nociceptive behavior in the 4T1-luc2 mouse model of bone cancer pain. We hypothesized that the analgesic mechanism of decitabine involved activation of the endogenous opioid system through demethylation and reexpression of the transcriptionally silenced endothelin B receptor gene, Ednrb. Indeed, Ednrb was hypermethylated and transcriptionally silenced in the mouse model of bone cancer pain. We demonstrated that expression of Ednrb in the cancer cells lead to release of β-endorphin in the cell supernatant, which reduced the number of responsive dorsal root ganglia neurons in an opioid-dependent manner. Our study supports a role of demethylating drugs, such as decitabine, as unique pharmacological agents targeting the pain in the cancer microenvironment.

Original languageEnglish (US)
Pages (from-to)619-631
Number of pages13
JournalPain
Volume160
Issue number3
DOIs
StatePublished - Mar 1 2019

Keywords

  • Bone cancer pain
  • DNA methylation
  • Decitabine
  • Ednrb
  • Endothelin receptor B
  • Endothelin-1

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Anesthesiology and Pain Medicine

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