Erin Nuray, Duymuş Ozlem, Oztürk Saffet, Demir Necdet
Department of Pharmacology, Akdeniz University, School of Medicine, Antalya 07070, Turkey.
Regul Pept. 2012 Nov 10;179(1-3):101-8. doi: 10.1016/j.regpep.2012.08.001. Epub 2012 Sep 11.
Chronic inflammation is involved in initiation as well as in progression of cancer. Semapimod, a tetravalent guanylhydrazon and formerly known as CNI-1493, inhibits the release of inflammatory cytokines from activated macrophages and this effect is partly mediated by the vagus nerve. Our previous findings demonstrated that inactivation of vagus nerve activity as well sensory neurons enhanced visceral metastasis of 4THM breast carcinoma. Hence semapimod by activating vagus nerve may inhibit breast cancer metastasis. Here, effects of semapimod on breast cancer metastasis, the role of vagal sensory neurons on this effect and changes in mediators of the neuroimmune connection, such as substance P (SP) as well as neprilysin-like activity, were examined. Vagotomy was performed on half of the control animals that were treated with semapimod following orthotopic injection of 4THM breast carcinoma cells. Semapimod decreased lung and liver metastases in control but not in vagotomized animals with an associated increased SP levels in sensory nerve endings. Semapimod also increased neprilysin-like activity in lung tissue of control animals but not in tumor-bearing animals. This is the first report demonstrating that semapimod enhances vagal sensory nerve activity and may have anti-tumoral effects under in-vivo conditions. Further studies, however, are required to elucidate the conditions and the mechanisms involved in anti-tumoral effects of semapimod.
慢性炎症参与癌症的起始和进展过程。司马莫德（Semapimod）是一种四价胍腙，以前称为CNI - 1493，它能抑制活化巨噬细胞释放炎性细胞因子，且这种作用部分由迷走神经介导。我们之前的研究结果表明，迷走神经活动以及感觉神经元失活会增强4THM乳腺癌的内脏转移。因此，司马莫德通过激活迷走神经可能抑制乳腺癌转移。在此，研究了司马莫德对乳腺癌转移的影响、迷走感觉神经元在此作用中的角色以及神经免疫连接介质（如P物质（SP）和中性内肽酶样活性）的变化。在原位注射4THM乳腺癌细胞后，对接受司马莫德治疗的一半对照动物进行了迷走神经切断术。司马莫德减少了对照动物的肺和肝转移，但在迷走神经切断的动物中没有这种作用，同时感觉神经末梢中的SP水平相应增加。司马莫德还增加了对照动物肺组织中的中性内肽酶样活性，但在荷瘤动物中没有增加。这是第一份表明司马莫德增强迷走感觉神经活动并可能在体内条件下具有抗肿瘤作用的报告。然而，需要进一步研究来阐明司马莫德抗肿瘤作用所涉及的条件和机制。
