Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.
Key Lab of Oral Clinical Medicine, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.
Anticancer Agents Med Chem. 2019;19(2):248-255. doi: 10.2174/1871520618666181029170605.
BACKGROUND: The Oral Squamous Cell Carcinoma (OSCC) is one of the most frequent cancer types. Failure of treatment of OSCC is potentially lethal because of local recurrence, regional lymph node metastasis, and distant metastasis. Chemotherapy plays a vital role through suppression of tumorigenesis. Cyclosporine A (CsA), an immunosuppressant drug, has been efficiently used in allograft organ transplant recipients to prevent rejection, and also has been used in a subset of patients with autoimmunity related disorders. The present study aims to investigate novel and effective chemotherapeutic drugs to overcome drug-resistance in the treatment of OSCC. METHODS: Cells were incubated in the standard way. Cell viability was assayed using the MTT assay. Cell proliferation was determined using colony formation assay. The cell cycle assay was performed using flow cytometry. Apoptosis was assessed using fluorescence-activated cell sorting after stained by the Annexin V-fluorescein isothiocyanate (FITC). Cell migration and invasion were analyzed using wound healing assay and tranwell. The effect of COX-2, c-Myc, MMP-9, MMP-2, and NFATc1 protein expression was determined using Western blot analysis while NFATc1 mRNA expression was determined by RT-PCR. RESULTS: In vitro studies indicated that CsA inhibited partial OSCC growth by inducing cell cycle arrest, apoptosis, and the migration and invasion of OSCC cells. We also demonstrated that CsA could inhibit the expression of NFATc1 and its downstream genes COX-2, c-Myc, MMP-9, and MMP-2 in OSCC cells. Furthermore, we analyzed the expression of NFATc1 in head and neck cancer through the Oncomine database. The data was consistent with the experimental findings. CONCLUSION: The present study initially demonstrated that CsA could inhibit the progression of OSCC cells and can mediate the signal molecules of NFATc1 signaling pathway, which has strong relationship with cancer development. That explains us CsA has potential to explore the possibilities as a novel chemotherapeutic drug for the treatment of OSCC.
背景：口腔鳞状细胞癌（OSCC）是最常见的癌症类型之一。由于局部复发、区域淋巴结转移和远处转移，OSCC 治疗失败可能是致命的。化疗通过抑制肿瘤发生起着至关重要的作用。环孢素 A（CsA）是一种免疫抑制剂药物，已在同种异体器官移植受者中有效地用于预防排斥反应，并且也已在一些自身免疫性疾病患者中使用。本研究旨在寻找新的有效的化疗药物来克服 OSCC 治疗中的耐药性。
方法：以标准方式孵育细胞。使用 MTT 测定法测定细胞活力。通过集落形成测定法测定细胞增殖。使用流式细胞术进行细胞周期分析。用 Annexin V-荧光素异硫氰酸酯（FITC）染色后通过荧光激活细胞分选术评估细胞凋亡。使用划痕愈合测定法和 Transwell 分析细胞迁移和侵袭。使用 Western blot 分析测定 COX-2、c-Myc、MMP-9、MMP-2 和 NFATc1 蛋白表达的影响，而 NFATc1 mRNA 表达则通过 RT-PCR 确定。
结果：体外研究表明，CsA 通过诱导细胞周期停滞、凋亡以及 OSCC 细胞的迁移和侵袭来抑制部分 OSCC 的生长。我们还表明，CsA 可以抑制 OSCC 细胞中 NFATc1 及其下游基因 COX-2、c-Myc、MMP-9 和 MMP-2 的表达。此外，我们通过 Oncomine 数据库分析了头颈部癌症中 NFATc1 的表达。该数据与实验结果一致。
结论：本研究初步表明，CsA 可以抑制 OSCC 细胞的进展，并可以介导 NFATc1 信号通路的信号分子，这与癌症的发展密切相关。这表明 CsA 有可能作为治疗 OSCC 的新型化疗药物进行探索。
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