Chen Hui, Li Lingyu, Lu Yunping, Shen Yajun, Zhang Min, Ge Lihua, Wang Min, Yang Jing, Tian Zhenchuan, Tang Xiaofei
Division of Oral Pathology, Beijing Institute of Dental Research, Beijing Stomatological Hospital & School of Stomatology, Capital Medical University, Beijing, People's Republic of China.
Cancer Manag Res. 2020 Nov 12;12:11573-11583. doi: 10.2147/CMAR.S280285. eCollection 2020.
The five-year survival rate of patients with oral cancer is approximately 50%; thus, alternative drugs with higher efficacy are urgently required. Azoxystrobin (AZOX), a natural, novel methoxyacrylate fungicide isolated from mushrooms, has a broad-spectrum, with highly efficient bactericidal effect. However, studies on AZOX have focused on antifungal effects. Here, we explore the potential cancer-preventive effects of AZOX and the underlying mechanisms.
The effects of AZOX on oral carcinogenesis induced by 4-nitroquinoline-1-oxide (4NQO) were investigated in C57BL/6 mice. Cell proliferation and apoptosis were examined by Ki67 immunohistochemistry and TUNEL staining, respectively. The main organ coefficients of each group were calculated to evaluate the biosafety of AZOX. CCK8 and flow cytometry were used to detect the effects of AZOX on cell viability and apoptosis in oral cancer cell line CAL27 and SCC15 cells in vitro. Cell cycle, mitochondrial complex III activity, intercellular reactive oxygen species (ROS) level, mitochondrial ROS level, and mitochondrial membrane potential (MMP) were detected by flow cytometry in AZOX-treated CAL27 cells.
AZOX significantly inhibited the occurrence of 4NQO-induced tongue cancer and delayed the progression of tongue precancerous lesions in mice. High-dose AZOX obviously inhibited cell viability and induced apoptosis in epithelial dysplastic and oral squamous cell carcinoma (OSCC) lesions in mouse tongue mucosa. AZOX was confirmed to have high biosafety. Similarly, in vitro cell viability was suppressed, and apoptosis was induced in AZOX-treated CAL27 and SCC15 cells. AZOX induced cell cycle arrest at the S phase. AZOX inhibited mitochondrial complex III activity, increased intracellular and mitochondrial ROS levels, and decreased MMP in CAL27 cells.
AZOX inhibited the development of oral cancer through specific inhibition of the activity of mitochondrial complex III, which led to ROS accumulation, and MMP decrease, ultimately inducing apoptosis. AZOX may be a novel agent for the prevention and treatment of OSCC.
口腔癌患者的五年生存率约为50%；因此，迫切需要疗效更高的替代药物。嘧菌酯（AZOX）是一种从蘑菇中分离出的天然新型甲氧基丙烯酸酯类杀菌剂，具有广谱、高效的杀菌作用。然而，对AZOX的研究主要集中在抗真菌作用上。在此，我们探讨AZOX潜在的癌症预防作用及其潜在机制。
在C57BL/6小鼠中研究AZOX对4-硝基喹啉-1-氧化物（4NQO）诱导的口腔致癌作用的影响。分别通过Ki67免疫组织化学和TUNEL染色检测细胞增殖和凋亡。计算每组的主要器官系数以评估AZOX的生物安全性。使用CCK8和流式细胞术检测AZOX对体外口腔癌细胞系CAL27和SCC15细胞活力和凋亡的影响。通过流式细胞术检测AZOX处理的CAL27细胞的细胞周期、线粒体复合物III活性、细胞内活性氧（ROS）水平、线粒体ROS水平和线粒体膜电位（MMP）。
AZOX显著抑制4NQO诱导的小鼠舌癌的发生，并延缓小鼠舌癌前病变的进展。高剂量AZOX明显抑制小鼠舌黏膜上皮发育异常和口腔鳞状细胞癌（OSCC）病变中的细胞活力并诱导凋亡。AZOX被证实具有高生物安全性。同样，在体外，AZOX处理的CAL27和SCC15细胞的细胞活力受到抑制并诱导凋亡。AZOX诱导细胞周期停滞在S期。AZOX抑制CAL27细胞中的线粒体复合物III活性，增加细胞内和线粒体ROS水平，并降低MMP。
AZOX通过特异性抑制线粒体复合物III的活性来抑制口腔癌的发展，这导致ROS积累和MMP降低，最终诱导凋亡。AZOX可能是一种预防和治疗OSCC的新型药物。
