Department of Anesthesiology, Baoan Central Hospital of Shenzhen, Shenzhen, Guangdong Province, China.
Department of Anesthesiology, Sichuan Academy of Medical Sicence & Sichuan Provincial People's Hospital, Electronic Science and Technology University, Chengdu, China.
Biochem Biophys Res Commun. 2019 Jul 5;514(4):1179-1184. doi: 10.1016/j.bbrc.2019.05.082. Epub 2019 May 16.
The biological effects of sevoflurane, a volatile anesthetics, on cancer cells seem to be contradictory and are not fully understood. While some studies demonstrate that sevoflurane promotes tumor growth, other studies report that sevoflurane displays anti-cancer activities. In this work, we systematically investigated the effects of sevoflurane at clinically relevant dose on the multiple biological aspects of cervical cancer cells and analyzed the underlying mechanism. Using a panel of cell lines, we found that sevoflurane significantly inhibited proliferation and migration of cervical cancer cells regardless of cellular origin and genetic background. In contrast, sevoflurane did not affect cervical cancer survival. Additionally, sevoflurane significantly enhanced chemosensitivity of cervical cancer cells. Mechanistically, we show that sevoflurane inhibits Ras and RhoA GTPase activities, leading to the blockade of their downstream signaling pathways, such as Ras/Erk/Akt and Rho/MYPT1/MLC. The rescue studies using Rho activator calpeptin or constitutively active Ras further confirm that Ras and RhoA are the targets of sevoflurane in cervical cancer. Interestingly, we found that the anti-proliferative effect of sevoflurane was via targeting Ras whereas the anti-migratory effect of sevoflurane was mediated via targeting RhoA. Our data clearly demonstrates the anti-cancer effects of sevoflurane. These findings provide preclinical evidence into the potential mechanisms by which sevoflurane may negatively affect cervical cancer growth and metastasis.
七氟醚是一种挥发性麻醉剂，其对癌细胞的生物学效应似乎相互矛盾，目前尚未完全阐明。虽然一些研究表明七氟醚促进肿瘤生长，但其他研究则表明七氟醚具有抗癌活性。在这项工作中，我们系统地研究了临床相关剂量的七氟醚对宫颈癌细胞多个生物学方面的影响，并分析了其潜在机制。使用一系列细胞系，我们发现七氟醚显著抑制了宫颈癌细胞的增殖和迁移，而与细胞起源和遗传背景无关。相比之下，七氟醚对宫颈癌细胞的存活没有影响。此外，七氟醚显著增强了宫颈癌细胞的化疗敏感性。从机制上讲，我们表明七氟醚抑制 Ras 和 RhoA GTP 酶活性，从而阻断其下游信号通路，如 Ras/Erk/Akt 和 Rho/MYPT1/MLC。使用 Rho 激活剂 calpeptin 或组成型激活 Ras 的挽救研究进一步证实，Ras 和 RhoA 是七氟醚在宫颈癌中的作用靶点。有趣的是，我们发现七氟醚的增殖抑制作用是通过靶向 Ras 实现的，而七氟醚的迁移抑制作用是通过靶向 RhoA 实现的。我们的数据清楚地表明了七氟醚的抗癌作用。这些发现为七氟醚可能对宫颈癌生长和转移产生负面影响的潜在机制提供了临床前证据。
