Demethylating drugs as novel analgesics for cancer pain.
Demethylating drugs as novel analgesics for cancer pain.
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DOI：
10.1158/1078-0432.ccr-14-0901
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发表时间：
2014-09-15
期刊：
影响因子：
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通讯作者：
Schmidt BL
中科院分区：
文献类型：
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作者：
Viet CT;Dang D;Ye Y;Ono K;Campbell RR;Schmidt BL
在这项研究中，我们评估了去甲基药物对口腔癌疼痛的镇痛潜力。虽然去甲基化药物可以影响许多基因的表达，但我们专注于μ阿片受体（OPRM 1）基因通路，因为它在疼痛处理中的作用。我们在小鼠口腔癌模型中确定了OPRM 1再表达的抗伤害感受作用。使用小鼠口腔癌模型，我们确定了去甲基化药物是否通过重新表达OPRM 1产生抗伤害感受。然后，我们用腺病毒转导重新表达OPRM 1，并确定OPRM 1重新表达是否产生抗伤害感受以及通过何种机制产生抗伤害感受。为了确定OPRM 1对癌症疼痛的临床意义，我们定量了口腔癌患者疼痛的癌组织和非疼痛的对侧正常组织以及口腔发育不良患者的非疼痛的发育不良组织中的OPRM 1甲基化。我们证明了OPRM 1在口腔癌患者的癌组织中甲基化，但在口腔发育不良患者的发育不良组织中没有甲基化。用去甲基化药物治疗导致小鼠癌症模型中的机械和热抗伤害感受。这种行为变化与癌症和相关神经元中的OPRM 1重新表达相关。类似地，腺病毒介导的OPRM 1在癌细胞上的重新表达导致纳洛酮可逆的抗伤害感受。在体外口腔癌细胞上的OPRM 1再表达增加了癌症的β-内啡肽分泌，并减少了用癌症上清液处理的神经元的活化。我们的研究确立了甲基化在癌症疼痛中的调节作用。癌细胞中OPRM 1的重新表达通过癌症介导的内源性阿片类物质分泌产生抗伤害作用。去甲基化药物具有涉及OPRM 1的镇痛作用。
In this study we evaluated the analgesic potential of demethylating drugs on oral cancer pain. While demethylating drugs could affect expression many genes, we focused on the mu-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. Using a mouse oral cancer model we determined whether demethylating drugs produced antinociception through re-expression of OPRM1. We then re-expressed OPRM1 with adenoviral transduction and determined if, and by what mechanism, OPRM1 re-expression produced antinociception. To determine the clinical significance of OPRM1 on cancer pain, we quantified OPRM1 methylation in painful cancer tissues and non-painful contralateral normal tissues of oral cancer patients, and non-painful dysplastic tissues of oral dysplasia patients. We demonstrated that OPRM1 was methylated in cancer tissue, but not normal tissue, of oral cancer patients, and not in dysplastic tissues from oral dysplasia patients. 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, adenoviral-mediated OPRM1 re-expression on cancer cells resulted in naloxone-reversible antinociception. OPRM1 re-expression on oral cancer cells in vitro increased beta-endorphin secretion from the cancer, and decreased activation of neurons that were treated with cancer supernatant. Our study establishes the regulatory role of methylation in cancer pain. OPRM1 re-expression in cancer cells produces antinociception through cancer-mediated endogenous opioid secretion. Demethylating drugs have an analgesic effect that involves OPRM1.