Samal Sabindra K, Routray Samapika, Veeramachaneni Ganesh Kumar, Dash Rupesh, Botlagunta Mahendran
1] Institute of Life Sciences, Bhubaneswar-751023, Odisha, India [2] Manipal University, Manipal-576104, Karnataka, India.
Department of Oral Pathology &Microbiology, Institute of Dental Sciences, 'Siksha O Anusandhan' University, Bhubaneswar-751003, Odisha, India.
Sci Rep. 2015 Apr 28;5:9982. doi: 10.1038/srep09982.
DDX3 belongs to DEAD box RNA helicase family and is involved in the progression of several types of cancer. In this work, we employed a High Throughput Virtual screening approach to identify bioactive compounds against DDX3 from ZINC natural database. Ketorolac salt was selected based on its binding free energy less than or equals to -5 Kcal/mol with reference to existing synthetic DDX3 inhibitors and strong hydrogen bond interactions as similar to crystallized DDX3 protein (2I4I). The anti-cancer activity of Ketorolac salt against DDX3 was tested using oral squamous cell carcinoma (OSCC) cell lines. This compound significantly down regulated the expression of DDX3 in human OSCC line (H357) and the half maximal growth inhibitory concentration (IC50) of Ketorolac salt in H357 cell line is 2.6 µM. Ketorolac salt also inhibited the ATP hydrolysis by directly interacting with DDX3. More importantly, we observed decreased number of neoplastic tongue lesions and reduced lesion severity in Ketorolac salt treated groups in a carcinogen induced tongue tumor mouse model. Taken together, our result demonstrates that Ketorolac salt is a newly discovered bioactive compound against DDX3 and this compound can be used as an ideal drug candidate to treat DDX3 associated oral cancer.
DDX3属于DEAD盒RNA解旋酶家族，参与多种癌症的进展。在这项研究中，我们采用高通量虚拟筛选方法，从ZINC天然数据库中鉴定针对DDX3的生物活性化合物。基于其与现有合成DDX3抑制剂相比结合自由能小于或等于-5千卡/摩尔，以及与结晶的DDX3蛋白（2I4I）相似的强氢键相互作用，选择了酮咯酸酯盐。使用口腔鳞状细胞癌（OSCC）细胞系测试了酮咯酸酯盐对DDX3的抗癌活性。该化合物显著下调了人OSCC细胞系（H357）中DDX3的表达，酮咯酸酯盐在H357细胞系中的半数最大生长抑制浓度（IC50）为2.6微摩尔。酮咯酸酯盐还通过直接与DDX3相互作用抑制ATP水解。更重要的是，在致癌物诱导的舌肿瘤小鼠模型中，我们观察到酮咯酸酯盐治疗组的肿瘤性舌病变数量减少，病变严重程度降低。综上所述，我们的结果表明酮咯酸酯盐是一种新发现的针对DDX3的生物活性化合物，该化合物可作为治疗DDX3相关口腔癌的理想候选药物。
