Department of Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Ruská 87, 110 00 Prague, Czech Republic.
Institute of Organic Chemistry and Biochemistry, Czech Academy of Science, Flemingovo náměstí 542/2, 166 10 Prague, Czech Republic.
Toxicol Appl Pharmacol. 2018 May 15;347:79-91. doi: 10.1016/j.taap.2018.04.002. Epub 2018 Apr 4.
We tested the role of substituents at the C3' and C3'N positions of the taxane molecule to identify taxane derivatives capable of overcoming acquired resistance to paclitaxel. Paclitaxel-resistant sublines SK-BR-3/PacR and MCF-7/PacR as well as the original paclitaxel-sensitive breast cancer cell lines SK-BR-3 and MCF-7 were used for testing. Increased expression of the ABCB1 transporter was found to be involved in the acquired resistance. We tested three groups of taxane derivatives: (1) phenyl group at both C3' and C3'N positions, (2) one phenyl at one of the C3' and C3'N positions and a non-aromatic group at the second position, (3) a non-aromatic group at both C3' and C3'N positions. We found that the presence of phenyl groups at both C3' and C3'N positions is associated with low capability of overcoming acquired paclitaxel resistance compared to taxanes containing at least one non-aromatic substituent at the C3' and C3'N positions. The increase in the ATPase activity of ABCB1 transporter after the application of taxanes from the first group was found to be somewhat higher than after the application of taxanes from the third group. Molecular docking studies demonstrated that the docking score was the lowest, i.e. the highest binding affinity, for taxanes from the first group. It was intermediate for taxanes from the second group, and the highest for taxanes from the third group. We conclude that at least one non-aromatic group at the C3' and C3'N positions of the taxane structure, resulting in reduced affinity to the ABCB1 transporter, brings about high capability of taxane to overcome acquired resistance of breast cancer cells to paclitaxel, due to less efficient transport of the taxane compound out of the cancer cells.
我们测试了紫杉醇分子的 C3'和 C3'N 位置取代基的作用，以确定能够克服紫杉醇获得性耐药的紫杉醇衍生物。使用紫杉醇耐药亚系 SK-BR-3/PacR 和 MCF-7/PacR 以及原始紫杉醇敏感乳腺癌细胞系 SK-BR-3 和 MCF-7 进行测试。发现 ABCB1 转运蛋白的表达增加与获得性耐药有关。我们测试了三组紫杉醇衍生物：（1）C3'和 C3'N 位置均为苯基，（2）C3'和 C3'N 位置之一为苯基，另一个位置为非芳基，（3）C3'和 C3'N 位置均为非芳基。我们发现，与含有至少一个非芳基取代基的 C3'和 C3'N 位置的紫杉醇相比，C3'和 C3'N 位置均为苯基的紫杉醇克服获得性紫杉醇耐药的能力较低。应用第一组紫杉醇后 ABCB1 转运蛋白的 ATPase 活性增加被发现略高于应用第三组紫杉醇后。分子对接研究表明，对接评分最低，即与第一组紫杉醇的结合亲和力最高。第二组的对接评分居中，第三组的对接评分最高。我们得出结论，紫杉醇结构的 C3'和 C3'N 位置至少有一个非芳基基团，导致与 ABCB1 转运蛋白的亲和力降低，使紫杉醇具有克服乳腺癌细胞对紫杉醇获得性耐药的高能力，因为紫杉醇化合物从癌细胞中排出的效率较低。
