The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, 430079, Wuhan, PR China.
The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, 430079, Wuhan, PR China; Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan, 430079, PR China.
Eur J Pharmacol. 2021 Jan 15;891:173757. doi: 10.1016/j.ejphar.2020.173757. Epub 2020 Nov 26.
Cancer stem cell therapy is becoming a focal point for oral squamous cell carcinoma (OSCC). They can be regulated by tumor glucose metabolism, whereas the regulation is not fully investigated in OSCC. Herein, we studied the synergistic anti-tumor effect of a LIN28 inhibitor C1632 and hypoglycemic medication metformin in OSCC. In this study, OSCC cell lines SCC9 and CAL27 were treated with C1632 and metformin respectively or synergistically. First, western blotting was performed to detect the expression level of LIN28 and its downstream molecule HMGA2. Second, MTT assay was conducted to assess cell proliferation. Next, wound healing assay and transwell assay were applied to evaluate cell migration. Then, xenograft mouse experiment was done to explore anti-tumor effect in vivo. Finally, western blotting was used to investigate the pharmacological mechanisms of the synergistic effect oft he two medication. Results showed that LIN28 and HMGA2 expression decreased significantly in SCC9 and CAL27 cells under 240 μM C1632 treatment for 72 h. These effects were synergized under combined treatment for 24 h. Cell proliferation ability and migration ability of both cell lines decreased significantly under respective and combined treatment. In xenograft mouse experiment, tumor weights decreased by 48% under 40 mg/kg/3d C1632 treatment, 53% under 250 mg/kg/d metformin treatment and 91% under combined treatment for 18 days. Tumor volumes decreased by 32%, 57% and 47% under C1632, metformin and combined treatment respectively. These results indicated that C1632 and metformin exerts synergistic anti-tumor effects in OSCC cell lines SCC9 and CAL27, and also inhibits xenograft tumor growth in vivo.
癌症干细胞治疗正成为口腔鳞状细胞癌（OSCC）的研究焦点。肿瘤葡萄糖代谢可以调节癌症干细胞，然而，OSCC 中的调节作用尚未完全研究清楚。在此，我们研究了 LIN28 抑制剂 C1632 和降血糖药物二甲双胍在 OSCC 中的协同抗肿瘤作用。在这项研究中，分别用 C1632 和二甲双胍及其联合处理 OSCC 细胞系 SCC9 和 CAL27。首先，通过 Western blot 检测 LIN28 及其下游分子 HMGA2 的表达水平。其次，通过 MTT 检测评估细胞增殖。接下来，进行划痕愈合实验和 Transwell 实验评估细胞迁移。然后，进行异种移植小鼠实验以探索体内抗肿瘤作用。最后，通过 Western blot 研究两种药物联合作用的药理学机制。结果表明，在 240 μM C1632 处理 72 小时后，SCC9 和 CAL27 细胞中的 LIN28 和 HMGA2 表达显著下降。联合处理 24 小时后，这些作用呈协同作用。两种细胞系的细胞增殖能力和迁移能力均显著下降。在异种移植小鼠实验中，40mg/kg/3d C1632 治疗组肿瘤重量降低 48%，250mg/kg/d 二甲双胍治疗组降低 53%，联合治疗组降低 91%，持续 18 天。肿瘤体积分别降低 32%、57%和 47%。这些结果表明，C1632 和二甲双胍在 OSCC 细胞系 SCC9 和 CAL27 中发挥协同抗肿瘤作用，并在体内抑制异种移植肿瘤生长。
