Hospital of Stomatology, Sun Yat-sen University, Guangzhou, PR, China; Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, PR, China; Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, PR, China.
Hospital of Stomatology, Sun Yat-sen University, Guangzhou, PR, China; Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, PR, China; Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, PR, China.
Biomed Pharmacother. 2021 Jul;139:111545. doi: 10.1016/j.biopha.2021.111545. Epub 2021 Apr 16.
Tacrolimus (TAC, FK506) is a major calcineurin inhibitor and has been commonly used in treatments of patients with organ transplants and immune diseases. Moreover, tacrolimus is recommended by the treatment guidelines for oral potentially malignant disorders (OPMDs) such as oral lichen planus (OLP). However, whether tacrolimus increases the risk of cancer remains controversial. We observed that in a 4-Nitroquinoline N-oxide (4NQO)-induced oral carcinogenesis model, tacrolimus treatment was associated with a significantly lower ratio of cancer formation (52.94% vs. 90%) and a lower proportion of Ki67 and proliferation cell nuclear antigen (PCNA) -positive cells in lesion areas (P < 0.001). Liver, kidney, and lung functions of rats and the tumor immune microenvironment of the tongue were not affected. These observations suggest that tacrolimus blocked oral carcinogenesis through epithelial cell proliferation inhibition, independent of its immunosuppressive effects. As a processing factor, tacrolimus decreased tumor formation and cell proliferation in different stages of oral squamous cell carcinoma (OSCC) progression in vivo and in vitro. Furthermore, we investigated effects on the cell cycle and expression of related proteins. Tacrolimus induced G1/S phase arrest and significantly downregulated the expression of cyclinD1, cyclinE1, and c-Myc. These results suggest that tacrolimus induces G1/S phase arrest via inhibition of cyclinD1, cyclinE1, and c-Myc expression and retards oral cell carcinogenesis in vitro and in vivo. Thus, application of tacrolimus is a safe therapeutic strategy for treating OPMDs.
他克莫司（TAC，FK506）是一种主要的钙调神经磷酸酶抑制剂，常用于治疗器官移植和免疫性疾病患者。此外，他克莫司被治疗口腔潜在恶性疾病（OPMDs）的指南推荐，如口腔扁平苔藓（OLP）。然而，他克莫司是否会增加癌症风险仍存在争议。我们观察到，在 4-硝基喹啉-N-氧化物（4NQO）诱导的口腔致癌模型中，他克莫司治疗与癌症形成比例显著降低（52.94% vs. 90%）以及病变区域 Ki67 和增殖细胞核抗原（PCNA）阳性细胞比例降低有关（P < 0.001）。大鼠的肝、肾和肺功能以及舌的肿瘤免疫微环境不受影响。这些观察结果表明，他克莫司通过抑制上皮细胞增殖来阻断口腔致癌作用，而不依赖于其免疫抑制作用。作为一种加工因子，他克莫司在体内和体外减少了不同阶段口腔鳞状细胞癌（OSCC）进展过程中的肿瘤形成和细胞增殖。此外，我们研究了对细胞周期和相关蛋白表达的影响。他克莫司诱导 G1/S 期阻滞，并显著下调 cyclinD1、cyclinE1 和 c-Myc 的表达。这些结果表明，他克莫司通过抑制 cyclinD1、cyclinE1 和 c-Myc 的表达诱导 G1/S 期阻滞，并在体内和体外延迟口腔细胞癌变。因此，他克莫司的应用是治疗 OPMDs 的一种安全治疗策略。
