Clinically relevant concentration of sevoflurane suppresses cervical cancer growth and migration through targeting multiple oncogenic pathways.

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.