School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India.
School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi 110067, India.
J Photochem Photobiol B. 2017 Feb;167:299-308. doi: 10.1016/j.jphotobiol.2017.01.010. Epub 2017 Jan 12.
Cancer, the second major cause of mortality trailing the cardiovascular diseases, is a multifactorial heterogeneous disease and growing public health problem worldwide. Owing to severe adverse effects of currently available therapies, there is a growing interest in natural compounds present in our daily diet. Among various natural products, flavonoids-polyphenolic compounds have attracted much attention and have been well-documented for their biological activities. Some flavonoids may inhibit cancer cell proliferation by modulating the action of different enzymes and signal transduction pathways. In the present study, we have evaluated the effect of pinostrobin, a natural flavonoid, on the catalytic activity of topoisomerase I, an essential enzyme for normal DNA replication. Catalytic inhibition of topoisomerase I activity would impair DNA replication of rapidly dividing cancer cells and hence inhibits tumor progression. Pinostrobin interaction with the topoisomerase I and DNA assessed in silico indicated it to form a ternary complex with both. In silico data also suggested pinostrobin to be an effective allosteric inhibitor for topoisomerase I. Further, in vitro investigations such as ethidium bromide displacement assay and spectroscopic studies supported in silico results on the binding of pinostrobin at the interface of topoisomerase I and DNA. Pinostrobin effectively inhibited topoisomerase I activity in vitro further confirming our in silico and in vitro findings. Since topoisomerase I is essential for DNA replication, inhibition of its activity by pinostrobin highlights the therapeutic potential of pinostrobin as an anti-proliferative agent.
癌症是继心血管疾病之后的第二大死亡原因，是一种多因素、异质性疾病，也是全球日益严重的公共卫生问题。由于现有治疗方法的严重副作用，人们对我们日常饮食中存在的天然化合物越来越感兴趣。在各种天然产物中，类黄酮——多酚类化合物引起了广泛关注，并因其生物活性而得到了充分的研究。一些类黄酮可以通过调节不同酶和信号转导途径的作用来抑制癌细胞增殖。在本研究中，我们评估了天然类黄酮 pinostrobin 对拓扑异构酶 I 催化活性的影响，拓扑异构酶 I 是正常 DNA 复制所必需的酶。拓扑异构酶 I 活性的催化抑制会损害快速分裂的癌细胞的 DNA 复制，从而抑制肿瘤的进展。Pinostrobin 与拓扑异构酶 I 和 DNA 的相互作用的计算机模拟表明，它与两者形成三元复合物。计算机模拟数据还表明，pinostrobin 是拓扑异构酶 I 的有效变构抑制剂。此外，溴化乙锭置换试验和光谱研究等体外研究支持了计算机模拟结果，表明 pinostrobin 结合在拓扑异构酶 I 和 DNA 的界面上。Pinostrobin 有效地抑制了体外拓扑异构酶 I 的活性，进一步证实了我们的计算机模拟和体外研究结果。由于拓扑异构酶 I 对 DNA 复制至关重要，因此 pinostrobin 抑制其活性突出了 pinostrobin 作为抗增殖剂的治疗潜力。
