Kim Ukjin, Shin Changsoo, Kim C-Yoon, Ryu Bokyeong, Kim Jin, Bang Junpil, Park Jae-Hak
Department of Laboratory Animal Medicine, Research Institute for Veterinary Science, BK21 PLUS Program for Creative Veterinary Science Research, College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of Korea.
Department of Energy Resources Engineering, Seoul National University, Seoul 08826, Republic of Korea.
Oncol Lett. 2021 May;21(5):395. doi: 10.3892/ol.2021.12656. Epub 2021 Mar 18.
Benzimidazole derivatives are used for their antihelmintic properties, but have also been reported to exert anticancer effects. In the present study, the anticancer effects of albendazole on prostate cancer cells were assessed using proliferation, clonogenic and migration assays. To investigate the anticancer mechanisms of albendazole, reactive oxygen species (ROS) levels were measured, and the expression of genes associated with oxidative stress and Wnt/β-catenin signaling was confirmed by reverse transcription-quantitative PCR and western blotting. Albendazole selectively inhibited the proliferation of the PC3, DU145, LNCaP and AT2 prostate cancer cell lines at concentrations that did not affect the proliferation of a normal prostate cell line (RWPE-1). Albendazole also inhibited the colony formation and migration of PC3 and DU145 cells, as well as inducing ROS production. Diphenyleneiodonium chloride, an inhibitor of NADPH oxidase (NOX), one of the sources of ROS, decreased basal ROS levels in the PC3 and DU145 cells, but did not reduce albendazole-associated ROS production, suggesting that ROS production following albendazole treatment was NOX-independent. The anticancer effect was decreased when albendazole-induced ROS was reduced by treatment with antioxidants (glutathione and N-acetylcysteine). Furthermore, albendazole decreased the mRNA expression of CDGSH iron sulfur domain 2, which regulates antioxidant activity against ROS, as well as the antioxidant enzymes catalase, and glutathione peroxidase 1 and 3. Albendazole also decreased the mRNA expression of catenin β1 and transcription factor 4, which regulate Wnt/β-catenin signaling and its associated targets, Twist family BHLH transcription factor 1 and BCL2. The albendazole-related decrease in the expression levels of oxidative stress-related genes and Wnt/β-catenin signaling proteins was thought to be associated with ROS production. These results suggest that the antihelmintic drug, albendazole, has inhibitory effects against prostate cancer cells . Therefore, albendazole may potentially be used as a novel anticancer agent for prostate cancer.
苯并咪唑衍生物因其抗蠕虫特性而被使用，但也有报道称其具有抗癌作用。在本研究中，使用增殖、克隆形成和迁移试验评估了阿苯达唑对前列腺癌细胞的抗癌作用。为了研究阿苯达唑的抗癌机制，测量了活性氧（ROS）水平，并通过逆转录定量PCR和蛋白质印迹法确认了与氧化应激和Wnt/β-连环蛋白信号相关的基因表达。阿苯达唑在不影响正常前列腺细胞系（RWPE-1）增殖的浓度下，选择性抑制了PC3、DU145、LNCaP和AT2前列腺癌细胞系的增殖。阿苯达唑还抑制了PC3和DU145细胞的集落形成和迁移，并诱导了ROS的产生。二苯基碘鎓氯化物是ROS来源之一NADPH氧化酶（NOX）的抑制剂，可降低PC3和DU145细胞中的基础ROS水平，但并未降低阿苯达唑相关的ROS产生，这表明阿苯达唑处理后ROS的产生不依赖于NOX。当用抗氧化剂（谷胱甘肽和N-乙酰半胱氨酸）处理降低阿苯达唑诱导的ROS时，抗癌效果降低。此外，阿苯达唑降低了调节针对ROS的抗氧化活性的CDGSH铁硫结构域2以及抗氧化酶过氧化氢酶、谷胱甘肽过氧化物酶1和3的mRNA表达。阿苯达唑还降低了调节Wnt/β-连环蛋白信号及其相关靶标Twist家族BHLH转录因子1和BCL2的连环蛋白β1和转录因子4的mRNA表达。阿苯达唑相关的氧化应激相关基因和Wnt/β-连环蛋白信号蛋白表达水平的降低被认为与ROS的产生有关。这些结果表明，抗蠕虫药物阿苯达唑对前列腺癌细胞具有抑制作用。因此，阿苯达唑可能有潜力用作前列腺癌的新型抗癌药物。
