Substituents at the C3' and C3'N positions are critical for taxanes to overcome acquired resistance of cancer cells to paclitaxel

0490321 - ÚOCHB 2019 RIV US eng J - Článek v odborném periodiku
Jelínek, M. - Balušíková, K. - Daniel, P. - Němcová-Fürstová, V. - Palani, Kirubakaran - Jaček, M. - Wei, L. - Wang, X. - Vondrášek, Jiří - Ojima, I. - Kovář, J.
Substituents at the C3' and C3'N positions are critical for taxanes to overcome acquired resistance of cancer cells to paclitaxel.
Toxicology and Applied Pharmacology. Roč. 347, May 15 (2018), s. 79-91. ISSN 0041-008X. E-ISSN 1096-0333
Institucionální podpora: RVO:61388963
Klíčová slova: taxane derivates * acquired resistance to paclitaxel * breast cancer cells * ABCB1 transporter * molecular docking
Obor OECD: Biochemistry and molecular biology
Impakt faktor: 3.585, rok: 2018

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.
Trvalý link: http://hdl.handle.net/11104/0284952