Background and Objectives: Sevoflurane, a widely used inhalational anesthetic, is frequently administered during hepatocellular carcinoma (HCC) surgery, including hepatic resection and orthotopic liver transplantation. Because such procedures often require prolonged anesthetic exposure, the potential influence of sevoflurane on HCC cell behavior is of clinical interest. We aimed to evaluate the effects of sevoflurane on the proliferation and migration of HepG2 cells in vitro and on tumor growth in a xenograft mouse model in vivo, and to explore whether hypoxia-inducible factor-1α (HIF-1α) might be involved in this process. Materials and Methods: For the in vitro experiments, HepG2 cells were exposed to room air (0%), 2%, or 4% sevoflurane. A scratch wound healing assay was used to assess cell migration, and the number of viable cells was quantified by hemocytometer counting on day 4 to estimate proliferation. For the in vivo experiments, BALB/c nude mice bearing HepG2 xenografts were exposed to room air, 2% sevoflurane, or 4% sevoflurane for 3 h, three times weekly for 5 weeks. Tumor size and tumor weight were measured at the end of the exposure period. HIF-1α protein levels in tumor tissue were measured by enzyme-linked immunosorbent assay (ELISA) in tumor lysates and normalized to total tumor protein as an exploratory mechanistic analysis. Given the small sample available for this endpoint, the analysis had limited sensitivity to detect modest differences. Results: When wound closure was quantified and pooled across the analyzable experiments, no statistically significant difference was detected among the room air, 2% sevoflurane, and 4% sevoflurane groups (day-2 closure 19.9 ± 32.1%, 22.1 ± 25.8%, and 22.3 ± 28.8%, respectively; repeated-measures ANOVA p = 0.82), with variability dominated by between-experiment rather than treatment differences. In the proliferation assay, the number of viable HepG2 cells on day 4 was significantly lower in the 2% sevoflurane group (62.6 ± 3.3 × 105) than in the room air group (68.5 ± 4.2 × 105; p < 0.05); the 4% sevoflurane group (66.0 ± 3.2 × 105) showed an intermediate value that did not reach statistical significance. In the xenograft model, mean tumor size in the room air, 2% sevoflurane, and 4% sevoflurane groups was 7.1 ± 1.9, 2.7 ± 2.0, and 2.1 ± 0.9 cm3, respectively (p = 0.041 for room air vs. 2% sevoflurane; p = 0.034 for room air vs. 4% sevoflurane). Tumor weight was likewise lower in the sevoflurane groups (room air, 7.88 ± 2.2 g; 2% sevoflurane, 2.95 ± 2.1 g; 4% sevoflurane, 2.3 ± 1.6 g; p = 0.044 for room air vs. 2% sevoflurane; p = 0.067 for room air vs. 4% sevoflurane). No statistically significant differences in tumor HIF-1α protein levels were observed among the three groups. Conclusions: In this exploratory study, sevoflurane exposure was associated with reduced HepG2 xenograft tumor growth in vivo, whereas its in vitro effects were more limited: a reduction in viable cell number was observed only at 2% sevoflurane, and an effect on cell migration could not be confirmed when analyzed across experiments. Tumor HIF-1α levels did not differ significantly between groups, suggesting that other molecular pathways may be involved. Further mechanistic and clinical studies are warranted before any conclusions can be drawn about the relevance of these findings to the perioperative management of patients with HCC.
Kim et al. (Tue,) studied this question.