Tiwari Amit, Gopalan Kutty N, Kumar Nitesh, Chaudhary Anil, Vasanth Raj P, Shenoy Rekha, Mallikarjuna Rao C
Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal, Karnataka, 576104, India.
Department of Pharmaceutical Biotechnology, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal, 576104, India.
Cytotechnology. 2016 Dec;68(6):2553-2565. doi: 10.1007/s10616-016-9979-9. Epub 2016 Jun 9.
The oxadiazole moiety is known for its anticancer activity through its antiangiogenic and mitostatic potential. Taking this as a cue, the present study was designed to investigate the anti-cancer potential of selected oxadiazole derivatives. Twelve 1,3,4-oxadiazole derivatives (AMK OX-1 to AMK OX-12) were synthesized and were tested for IC values through brine shrimp lethality assay and MTT assay on HeLa and A549 cell lines. Four compounds, AMK OX-8, 9, 11 and 12 showed potential cytotoxicity activity with low IC value. These compounds produced considerable cytotoxic effect on Hep-2 and A549 cancer cell lines. However, they were found to be comparatively safer to normal cell lines, viz., V-79 cell lines than to the tested cancer cell lines, such as HeLa, A 549, and Hep2 cell lines. The mechanism of cytotoxicity was evaluated through nuclear staining and DNA ladder assay. Although DNA ladder assay showed DNA fragmentation (apoptotic phenomenon) in Hep-2 cells treated with only AMK OX-12, the staining procedures using acridine orange, ethidium bromide and propidium iodide showed apoptotic bodies in cells treated with AMK OX-8, 9 and 12 also. In JCI staining on isolated mitochondria of Hep2 cells, AMK OX-8, 9-11 and 12 displayed increasing fluorescence intensity with time which confirmed involvement of mitochondrial pathway and intrinsic pathway of apoptosis. All four compounds were found to be safe in acute oral toxicity study in Swiss albino mice. These derivatives were effective in reducing tumor size and weight in the in vivo DLA-induced solid tumor model. They were found to be significantly effective in reducing tumor volume and tumor weight.
恶二唑部分因其抗血管生成和有丝分裂抑制潜力而具有抗癌活性。以此为线索，本研究旨在调查所选恶二唑衍生物的抗癌潜力。合成了12种1,3,4-恶二唑衍生物（AMK OX-1至AMK OX-12），并通过卤虫致死率测定法以及对HeLa和A549细胞系进行MTT测定来检测其IC值。四种化合物AMK OX-8、9、11和12显示出具有低IC值的潜在细胞毒性活性。这些化合物对Hep-2和A549癌细胞系产生了相当大的细胞毒性作用。然而，发现它们对正常细胞系即V-79细胞系的安全性相对高于对所测试的癌细胞系，如HeLa、A549和Hep2细胞系。通过核染色和DNA梯状条带分析评估细胞毒性机制。尽管DNA梯状条带分析显示仅用AMK OX-12处理的Hep-2细胞中存在DNA片段化（凋亡现象），但使用吖啶橙、溴化乙锭和碘化丙啶的染色程序也显示在用AMK OX-8、9和12处理的细胞中存在凋亡小体。在对Hep2细胞分离的线粒体进行的JCI染色中，AMK OX-8、9 - 11和12随时间显示出荧光强度增加，这证实了线粒体途径和凋亡内在途径的参与。在瑞士白化小鼠的急性口服毒性研究中发现所有四种化合物都是安全的。在体内DLA诱导的实体瘤模型中，这些衍生物在减小肿瘤大小和重量方面有效。发现它们在减小肿瘤体积和肿瘤重量方面具有显著效果。
