Department of Medical Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona (A.L.T., S.A.G., H.A.C., N.B., T.M.L.-M., T.W.V); Division of Pain Medicine, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland (S.A.G.); and The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California (M.J.N., B.F.C.).
Department of Medical Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona (A.L.T., S.A.G., H.A.C., N.B., T.M.L.-M., T.W.V); Division of Pain Medicine, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland (S.A.G.); and The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California (M.J.N., B.F.C.)
J Pharmacol Exp Ther. 2020 May;373(2):230-238. doi: 10.1124/jpet.119.262337. Epub 2020 Feb 13.
Metastatic breast cancer is prevalent worldwide, and one of the most common sites of metastasis is long bones. Of patients with disease, the major symptom is pain, yet current medications fail to adequately result in analgesic efficacy and present major undesirable adverse effects. In our study, we investigate the potential of a novel monoacylglycerol lipase (MAGL) inhibitor, MJN110, in a murine model of cancer-induced bone pain. Literature has previously demonstrated that MAGL inhibitors function to increase the endogenous concentrations of 2-arachydonylglycerol, which then activates CB1 and CB2 receptors to inhibit inflammation and pain. We demonstrate that administration of MJN110 significantly and dose dependently alleviates spontaneous pain behavior during acute administration compared with vehicle control. In addition, MJN110 maintains its efficacy in a chronic-dosing paradigm over the course of 7 days without signs of receptor sensitization. In vitro analysis of MJN110 demonstrated a dose-dependent and significant decrease in cell viability and proliferation of 66.1 breast adenocarcinoma cells to a greater extent than KML29, an alternate MAGL inhibitor, or the CB2 agonist JWH015. Chronic administration of the compound did not appear to affect tumor burden, as evidenced by radiograph or histologic analysis. Together, these data support the application for MJN110 as a novel therapeutic for cancer-induced bone pain. SIGNIFICANCE STATEMENT: Current standard of care for metastatic breast cancer pain is opioid-based therapies with adjunctive chemotherapy, which have highly addictive and other deleterious side effects. The need for effective, non-opioid-based therapies is essential, and harnessing the endogenous cannabinoid system is proving to be a new target to treat various types of pain conditions. We present a novel drug targeting the endogenous cannabinoid system that is effective at reducing pain in a mouse model of metastatic breast cancer to bone.
转移性乳腺癌在全球范围内普遍存在，其中最常见的转移部位之一是长骨。患有这种疾病的患者主要症状是疼痛，但目前的药物无法有效地产生镇痛效果，并存在主要的不良副作用。在我们的研究中，我们研究了一种新型单酰基甘油脂肪酶 (MAGL) 抑制剂 MJN110 在癌症诱导性骨痛的小鼠模型中的潜力。文献先前表明，MAGL 抑制剂的作用是增加内源性 2-花生四烯酰甘油的浓度，然后激活 CB1 和 CB2 受体以抑制炎症和疼痛。我们证明，与载体对照相比，MJN110 的给药在急性给药期间显著且剂量依赖性地缓解自发性疼痛行为。此外，MJN110 在 7 天的慢性给药方案中保持其疗效，而没有受体敏化的迹象。MJN110 的体外分析表明，与替代 MAGL 抑制剂 KML29 或 CB2 激动剂 JWH015 相比，细胞活力和 66.1 乳腺癌腺癌细胞的增殖呈剂量依赖性显著降低。该化合物的慢性给药似乎不会影响肿瘤负担，这可以通过 X 射线或组织学分析来证明。总之，这些数据支持将 MJN110 作为一种新型治疗癌症诱导性骨痛的药物的应用。
转移性乳腺癌疼痛的当前标准治疗方法是基于阿片类药物的疗法，辅以化疗，但具有高度成瘾性和其他有害的副作用。需要有效的、非阿片类药物的治疗方法是至关重要的，利用内源性大麻素系统被证明是治疗各种类型疼痛的新目标。我们提出了一种新的药物，靶向内源性大麻素系统，在转移性乳腺癌向骨转移的小鼠模型中有效减轻疼痛。
