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

Appel, Camilla Kristinea; Scheff, Nicole Newellb; Viet, Chi Tonglienb; Schmidt, Brian Leeb; Heegaard, Anne-Mariea,*

doi: 10.1097/j.pain.0000000000001442
Research Paper
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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.

Decitabine attenuates nociception in a mouse model of bone cancer pain through demethylation and reexpression of the endothelin B receptor gene in the cancer microenvironment.

aFaculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

bBluestone Center for Clinical Research, New York University, New York, NY, United States

Corresponding author. Address: Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, Copenhagen Ø, DK-2100, Denmark. Tel.: (+45) 35 33 63 22. E-mail address: amhe@sund.ku.dk (A.-M. Heegaard).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

B.L. Schmidt and A.-M. Heegaard share the last authorship.

Received February 07, 2018

Received in revised form October 29, 2018

Accepted November 04, 2018

© 2019 International Association for the Study of Pain
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