Department of Biochemistry, Indian Institute of Science, Bangalore 560 012, India.
Institute of Bioinformatics and Applied Biotechnology, Electronic City, Bangalore 560 100, India.
Sci Rep. 2016 Oct 17;6:34653. doi: 10.1038/srep34653.
Resveratrol is one of the most widely studied bioactive plant polyphenols which possesses anticancer properties. Previously we have reported synthesis, characterization and identification of a novel resveratrol analog, SS28. In the present study, we show that SS28 induced cytotoxicity in several cancer cell lines ex vivo with an IC value of 3-5 μM. Mechanistic evaluation of effect of SS28 in non-small cell lung cancer cell line (A549) and T-cell leukemic cell line (CEM) showed that it inhibited Tubulin polymerization during cell division to cause cell cycle arrest at G2/M phase of the cell cycle at 12-18 h time period. Immunofluorescence studies confirmed the mitotic arrest upon treatment with SS28. Besides, we show that SS28 binds to Tubulin with a dissociation constant of 0.414 ± 0.11 μM. Further, SS28 treatment resulted in loss of mitochondrial membrane potential, activation of Caspase 9 and Caspase 3, leading to PARP-1 cleavage and finally cell death via intrinsic pathway of apoptosis. Importantly, treatment with SS28 resulted in regression of tumor in mice. Hence, our study reveals the antiproliferative activity of SS28 by disrupting microtubule dynamics by binding to its cellular target Tubulin and its potential to be developed as an anticancer molecule.
白藜芦醇是研究最广泛的生物活性植物多酚之一，具有抗癌特性。此前，我们已经报道了一种新型白藜芦醇类似物 SS28 的合成、表征和鉴定。在本研究中，我们表明 SS28 在几种癌细胞系中具有细胞毒性，IC 值为 3-5μM。对非小细胞肺癌细胞系（A549）和 T 细胞白血病细胞系（CEM）中 SS28 作用的机制评估表明，它在细胞分裂过程中抑制微管聚合，导致细胞周期停滞在细胞周期的 G2/M 期，在 12-18 小时的时间内。免疫荧光研究证实了 SS28 处理后的有丝分裂停滞。此外，我们表明 SS28 与微管的解离常数为 0.414±0.11μM。此外，SS28 处理导致线粒体膜电位丧失，Caspase 9 和 Caspase 3 激活，导致 PARP-1 裂解，最终通过细胞凋亡的内在途径导致细胞死亡。重要的是，SS28 的治疗导致小鼠肿瘤消退。因此，我们的研究通过结合其细胞靶标微管蛋白破坏微管动力学揭示了 SS28 的抗增殖活性，并且具有作为抗癌分子的潜力。
