Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal.
Department of Pharmaceutical Sciences and Medicines, Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal.
Int J Mol Sci. 2023 Mar 22;24(6):6004. doi: 10.3390/ijms24066004.
The natural polyphenolic compound Rottlerin (RoT) showed anticancer properties in a variety of human cancers through the inhibition of several target molecules implicated in tumorigenesis, revealing its potential as an anticancer agent. Aquaporins (AQPs) are found overexpressed in different types of cancers and have recently emerged as promising pharmacological targets. Increasing evidence suggests that the water/glycerol channel aquaporin-3 (AQP3) plays a key role in cancer and metastasis. Here, we report the ability of RoT to inhibit human AQP3 activity with an IC in the micromolar range (22.8 ± 5.82 µM for water and 6.7 ± 2.97 µM for glycerol permeability inhibition). Moreover, we have used molecular docking and molecular dynamics simulations to understand the structural determinants of RoT that explain its ability to inhibit AQP3. Our results show that RoT blocks AQP3-glycerol permeation by establishing strong and stable interactions at the extracellular region of AQP3 pores interacting with residues essential for glycerol permeation. Altogether, our multidisciplinary approach unveiled RoT as an anticancer drug against tumors where AQP3 is highly expressed providing new information to aquaporin research that may boost future drug design.
天然多酚化合物 Rottlerin（RoT）通过抑制几种与肿瘤发生相关的靶分子，在多种人类癌症中显示出抗癌特性，这表明其具有作为抗癌剂的潜力。水通道蛋白（AQPs）在不同类型的癌症中过度表达，最近已成为有前途的药理学靶点。越来越多的证据表明，水/甘油通道水通道蛋白-3（AQP3）在癌症和转移中发挥关键作用。在这里，我们报告了 RoT 抑制人 AQP3 活性的能力，其 IC 处于微摩尔范围（水为 22.8 ± 5.82 µM，甘油通透性抑制为 6.7 ± 2.97 µM）。此外，我们还使用分子对接和分子动力学模拟来了解解释其抑制 AQP3 能力的 RoT 的结构决定因素。我们的结果表明，RoT 通过在 AQP3 孔的细胞外区域建立与甘油渗透必需残基相互作用的强而稳定的相互作用来阻断 AQP3-甘油渗透。总之，我们的多学科方法揭示了 RoT 作为一种针对高度表达 AQP3 的肿瘤的抗癌药物，为水通道蛋白研究提供了新信息，可能会推动未来的药物设计。
