Bupivacaine inhibits the malignant biological behavior of oral squamous cell carcinoma cells by inhibiting the activation of ERK1/2 and STAT3

Oral squamous cell carcinoma (OSCC) is an aggressive malignant tumor. Bupivacaine (Bupi), a local anesthetic drug, has been shown to display anti-tumor activity against a variety of tumors.

Bupi could be used as an anticancer drug against the growth and stemness ability of OSCC. The underlying mechanism may be due to down-regulation of STAT3 and ERK1/2 signaling. This study provides a new insight for the application of Bupi.

We selected OSCC CAL-27 cells as the in vitro model. Cell toxicity, proliferation, apoptosis, and stemness were conducted, respectively. The protein levels of Ki67, PCNA, caspase-3, caspase-9, survivin, SOX2, NANOG, OCT4, STAT3, p-STAT3, ERK1/2, and p-ERK1/2 were evaluated by western blotting. Male BALB/c nude mice xenograft model was used to evaluate the effect of Bupi on tumor growth in vivo.

Compared with the control group, Bupi (0.2, 0.5, or 1 µm) significantly decreased the cell viability and the proliferation of CAL-27 cells. Meanwhile, Bupi significantly promoted apoptosis of CAL-27 cells compared with the control group. Additionally, Bupi inhibited the stemness of CAL-27 cells which was evidenced by a sphere formation assay. Bupi decreased the phosphorylation level of STAT3 and ERK1/2 in a dose-dependent manner. The addition of interferon-γ (IFN-γ, 20 ng/mL) in the experiment verified the role of Bupi on STAT3 and ERK1/2 signaling. In vivo, Bupi (40 µmol/kg) obviously suppressed the weight and size of the xenograft tumor, the number of apoptotic cells and Ki67+ decreased. Also, Bupi treatment inhibited the expression of stem-like marker proteins. Conclusions: Bupi could be used as an anticancer drug against the growth and stemness ability of OSCC. The underlying mechanism may be due to down-regulation of STAT3 and ERK1/2 signaling. This study provides a new insight for the application of Bupi.