Institute of Physiology, Faculty of Medicine, Comenius University Bratislava, Bratislava, Slovakia.
Biomedical Research Center, Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovakia.
Neoplasma. 2023 Jun;70(3):375-389. doi: 10.4149/neo_2023_230418N216.
Experimental and clinical data have shown that the nervous system can significantly stimulate the initiation and progression of melanoma. In support of this, approaches that reduce the transmission of signals from peripheral nerves to effector tissues reduce the recurrence of melanoma. Therefore, we investigated the effect of topical application of the local anesthetic Pliaglis (7% lidocaine and 7% tetracaine) on the growth of melanoma induced by intradermal application of B16F0 cells in mice without treatment and in mice treated with the anti-PD-1 antibody. We found that application of Pliaglis to melanoma significantly reduced its growth and this effect was even pronounced in mice treated with the anti-PD-1 antibody. To determine the mechanisms and pathways responsible for the observed effect, the in vitro effect of incubating melanoma cells with lidocaine and/or tetracaine and the in vivo gene expression of cancer and immune-related factors, percentage of immune cells, gene expression of selected neurotransmitter receptors and nerve growth factors in melanoma tissue were studied. We found that lidocaine and tetracaine significantly reduced the viability of B16F0 cells in vitro. In mice with melanoma, Pliaglis potentiated the effect of anti-PD-1 antibody on gene expression of COX-2, IL-1β, IL-6, CCL11, F4/80, CD206, and NCR1. In addition, Pliaglis increased the gene expression of α9nACHR and 5-HT2a receptors and decreased the gene expression of nerve growth factor receptor (p75NTR) and p53. We also observed Pliaglis-mediated changes in myeloid populations. Topical application of this local anesthetic cream decreased the CD11b+Gr1- population and increased the CD11b+Gr1high population. Our data suggest that Pliaglis reduces melanoma growth through a direct effect on melanoma cells as well as through modulation of the immune response. The involvement of nervous system-related signaling in the inhibitory effect of Pliaglis on melanoma is inconclusive from our data.
实验和临床数据表明，神经系统可以显著刺激黑色素瘤的发生和进展。支持这一点的是，减少外周神经向效应组织传递信号的方法可以减少黑色素瘤的复发。因此，我们研究了局部麻醉剂 Pliaglis（7%利多卡因和 7%丁卡因）在未经治疗和接受抗 PD-1 抗体治疗的小鼠中对 B16F0 细胞皮内注射诱导的黑色素瘤生长的影响。我们发现，Pliaglis 应用于黑色素瘤可显著抑制其生长，而在接受抗 PD-1 抗体治疗的小鼠中，这种作用更为明显。为了确定观察到的作用的机制和途径，我们研究了孵育黑色素瘤细胞与利多卡因和/或丁卡因的体外作用以及癌症和免疫相关因子、免疫细胞百分比、黑色素瘤组织中选定的神经递质受体和神经生长因子的基因表达。我们发现利多卡因和丁卡因可显著降低 B16F0 细胞的体外活力。在患有黑色素瘤的小鼠中，Pliaglis 增强了抗 PD-1 抗体对 COX-2、IL-1β、IL-6、CCL11、F4/80、CD206 和 NCR1 的基因表达的作用。此外，Pliaglis 增加了α9nACHR 和 5-HT2a 受体的基因表达，降低了神经生长因子受体（p75NTR）和 p53 的基因表达。我们还观察到 Pliaglis 介导的髓样细胞群变化。局部麻醉乳膏的应用降低了 CD11b+Gr1-群体，增加了 CD11b+Gr1high 群体。我们的数据表明，Pliaglis 通过直接作用于黑色素瘤细胞以及调节免疫反应来减少黑色素瘤的生长。我们的数据尚不能确定神经系统相关信号在 Pliaglis 对黑色素瘤的抑制作用中的作用。
