洛那法尼对甲状腺未分化癌细胞及裸鼠移植瘤具有抑制作用OA

Objective:To investigate the inhibitory effect of the farnesyltransferase inhibitor lonafarnib on anaplastic thyroid carcinoma(ATC),and to elucidate the underlying mechanisms.Methods:The anti-proliferative effect of lonafarnib on ATC cell lines(8505C,CAL62)was assessed using CCK-8 assay.Cell migration and invasion were evaluated by Transwell assay.Apoptosis was detected by flow cytometry.Western blotting was used to measure protein expression levels of Ras,extracellular signal-regulated kinase(ERK),phosphorylated ERK,poly ADP-ribose polymerase(PARP),cleaved PARP,cysteine aspartic acid specific protease-3(Caspase-3),cleaved Caspase-3,gasdermin E(GSDME),and GSDME N-terminal fragment(GSDME-N).A subcutaneous xenograft model was established in female BALB/c nude mice(4-6 weeks old).8505C cells(1×106)were injected into the right back of each mouse.When tumor volume reached 100-150 mm3,the mice were randomly divided into three groups(n=4 per group):blank control(normal saline by gavage every other day),low-dose lonafarnib(25 mg/kg by gavage every other day),and high-dose lonafarnib(50 mg/kg by gavage every other day).Treatment lasted for 15 days.Tumor volume and body weight were measured every two days.At the endpoint,tumors were excised and weighed.Results:Lonafarnib significantly inhibited the proliferation of ATC cells in a concentration-dependent manner,with superior efficacy compared to cobimetinib and lenvatinib.After treatment with 5,10,and 20 μmol/L lonafarnib,the numbers of migrated and invaded 8505C and CAL62 cells were markedly reduced,and the apoptosis rates were increased(all P<0.05).Mechanistically,lonafarnib treatment in ATC cells downregulated Ras protein expression,decreased the levels of total ERK,phosphorylated ERK,and PARP,and led to overall decreasing trends in Caspase-3 and GSDME expression.Concurrently,cleaved PARP increased in a concentration-and time-dependent manner,and both GSDME-N and cleaved Caspase-3 levels showed overall increasing trends.In vivo,the low-dose and high-dose lonafarnib groups exhibited significantly slower tumor growth compared with the control group.At the end of the observation period,tumor weights in lonafarnib groups were significantly lower than that in the control group(both P<0.05).No significant body weight loss was observed,indicating good tolerability.Conclusions:Lonafarnib effectively suppresses the malignant progression of ATC both in ATC cell lines and in a BALB/c nude mouse xenograft model.The mechanism involves inhibition of Ras farnesylation and the downstream ERK signaling pathway,leading to activation of Caspase-3/PARP-mediated apoptosis and GSDME-mediated pyroptosis.