Antitumor Activity of Lankacidin Group Antibiotics Is Due to Microtubule Stabilization via a Paclitaxel-like Mechanism
Antitumor Activity of Lankacidin Group Antibiotics Is Due to Microtubule Stabilization via a Paclitaxel-like Mechanism
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DOI：
10.1021/acs.jmedchem.6b01264
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发表时间：
2016-10-27
影响因子：
7.3
通讯作者：
Tuszynski, Jack
中科院分区：
文献类型：
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作者：
Ayoub, Ahmed Taha;Abou El-Magd, Rabab M.;Tuszynski, Jack
Lankacidin类抗生素对多种革兰氏阳性菌具有较强的抗菌活性。此外，它们显示出对某些细胞系模型具有相当大的抗肿瘤活性。几十年来，lankacidin的抗肿瘤活性与其抗微生物作用机制有关，这是在蛋白质合成过程中对肽键形成的干扰。然而，这一点从未得到实验证实。由于在先前的计算虚拟筛选研究中与紫杉醇样命中的显著相似性，我们认为兰卡菌素的细胞毒性作用是由于紫杉醇样作用。在这项研究中，我们测试了这一假设的计算和实验，并证实lankacidin是一种微管稳定剂，增强微管蛋白的组装和取代紫杉醇从其结合位点。本研究为优化lankacidin衍生物以获得更好的抗肿瘤活性奠定了基础。它还强调了计算预测的力量及其在指导实验和制定严格假设方面的帮助。
Lankacidin group antibiotics show strong antimicrobial activity against various Gram-positive bacteria. In addition, they were shown to have considerable antitumor activity against certain cell line models. For decades, the antitumor activity of lankacidin was associated with the mechanism of its antimicrobial action, which is interference with peptide bond formation during protein synthesis. This, however, was never confirmed experimentally. Due to significant similarity to paclitaxel-like hits in a previous computational virtual screening study, we suggested that the cytotoxic effect of lankacidin is due to a paclitaxel-like action. In this study, we tested this hypothesis computationally and experimentally and confirmed that lankacidin is a microtubule stabilizer that enhances tubulin assembly and displaces taxoids from their binding site. This study serves as a starting point for optimization of lankacidin derivatives for better antitumor activities. It also highlights the power of computational predictions and their aid in guiding experiments and formulating rigorous hypotheses.