Li Pengcheng, Zheng Xun, Shou Kangquan, Niu Yahui, Jian Chao, Zhao Yong, Yi Wanrong, Hu Xiang, Yu Aixi
Department of Orthopedics, Zhongnan Hospital of Wuhan University Wuhan 430071, Hubei, China.
Department of Orthopedics, Zhongnan Hospital of Wuhan UniversityWuhan 430071, Hubei, China; Molecular Imaging Program at Stanford, Canary Center at Stanford for Cancer Early Detection, Department of Radiology and Bio-X Program, Stanford UniversityStanford, CA, USA.
Am J Transl Res. 2016 Dec 15;8(12):5370-5385. eCollection 2016.
Di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT), the novel iron chelator, has been reported to inhibit the tumorigenesis and progression of various cancer cells, including neuroblastoma, neuroepithelioma and prostate cancer. However, whether Dp44mT has anticancer effects in osteosarcoma is still unknown. Here, we investigated the antitumor action of Dp44mT in osteosarcoma and its underlying mechanisms. A human osteosarcoma 143B cell line and 143B xenograft in nude mice were utilized, the anticancer effects of Dp44mT were examined through methods of MTT assay, transwell, wound healing assay, flow cytometry, western blot, immunohistochemistry and H&E staining. We showed that Dp44mT inhibits cell proliferation, invasion and migration . In addition, flow cytometry further illustrated that Dp44mT suppression of 143B cell proliferation, invasion and migration were partially due to induction of cell apoptosis, cell cycle arrest in S phase and ROS production. Also and , the expression levels of Bcl2, Bax, Caspase3, Caspase9, LC3-II, β-catenin and its downstream targets such as C-myc and Cyclin D1 demonstrated that cell apoptosis and autophagy, as well as Wnt/β-catenin pathway were involved in Dp44mT induced osteosarcoma suppression. The Dp44mT inhibition of osteosarcoma was further verified via animal models. The findings indicated that Dp44mT showed a significant reduction in the 143B xenograft tumor growth and metastasis. In conclusion, our data demonstrated that Dp44mT has effective anticancer capability in osteosarcoma and that may represent a promising treatment strategy for osteosarcoma.
二 - 2 - 吡啶酮 - 4,4 - 二甲基 - 3 - 硫代半卡巴腙（Dp44mT）是一种新型铁螯合剂，据报道可抑制包括神经母细胞瘤、神经上皮瘤和前列腺癌在内的多种癌细胞的肿瘤发生和进展。然而，Dp44mT在骨肉瘤中是否具有抗癌作用仍不清楚。在此，我们研究了Dp44mT在骨肉瘤中的抗肿瘤作用及其潜在机制。我们使用了人骨肉瘤143B细胞系和143B裸鼠异种移植模型，通过MTT法、Transwell实验、伤口愈合实验、流式细胞术、蛋白质免疫印迹法、免疫组织化学和苏木精 - 伊红染色等方法检测Dp44mT的抗癌效果。我们发现Dp44mT可抑制细胞增殖、侵袭和迁移。此外，流式细胞术进一步表明，Dp44mT对143B细胞增殖、侵袭和迁移的抑制作用部分归因于诱导细胞凋亡、使细胞周期停滞于S期以及产生活性氧。同样，Bcl2、Bax、Caspase3、Caspase9、LC3 - II、β - 连环蛋白及其下游靶点如C - myc和细胞周期蛋白D1的表达水平表明，细胞凋亡和自噬以及Wnt/β - 连环蛋白信号通路参与了Dp44mT诱导的骨肉瘤抑制过程。通过动物模型进一步验证了Dp44mT对骨肉瘤的抑制作用。研究结果表明，Dp44mT可显著降低143B异种移植瘤的生长和转移。总之，我们的数据表明Dp44mT在骨肉瘤中具有有效的抗癌能力，这可能代表了一种有前景的骨肉瘤治疗策略。
