Cancer Therapy: Preclinical Demethylating Drugs as Novel Analgesics for Cancer Pain

Purpose: In this study, we evaluated the analgesic potential of demethylating drugs on oral cancer pain. Althoughdemethylating drugs could affect expressionofmany genes,we focused on themu-opioid receptor (OPRM1) gene pathway, because of its role in pain processing. We determined the antinociceptive effect of OPRM1 re-expression in a mouse oral cancer model. Experimental Design: Using a mouse oral cancer model, we determined whether demethylating drugs produced antinociception through re-expression ofOPRM1. We then re-expressedOPRM1with adenoviral transduction and determined if, and by whatmechanism,OPRM1 re-expression produced antinociception. To determine the clinical significance of OPRM1 on cancer pain, we quantified OPRM1 methylation in painful cancer tissues and nonpainful contralateral normal tissues of patients with oral cancer, and nonpainful dysplastic tissues of patients with oral dysplasia. Results:Wedemonstrated thatOPRM1wasmethylated in cancer tissue, but not normal tissue, of patients with oral cancer, and not in dysplastic tissues frompatients with oral dysplasia. Treatment with demethylating drugs resulted in mechanical and thermal antinociception in the mouse cancer model. This behavioral change correlated with OPRM1 re-expression in the cancer and associated neurons. Similarly, adenoviralmediatedOPRM1 re-expression on cancer cells resulted in naloxone-reversible antinociception.OPRM1 reexpression on oral cancer cells in vitro increased b-endorphin secretion from the cancer, and decreased activation of neurons that were treated with cancer supernatant. Conclusion:Our study establishes the regulatory roleofmethylation in cancer pain.OPRM1 re-expression in cancer cells produces antinociception through cancer-mediated endogenous opioid secretion. Demethylating drugs have an analgesic effect that involvesOPRM1. Clin Cancer Res; 20(18); 4882–93. 2014 AACR.