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

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11120%2F18%3A43916572" target="_blank" >RIV/00216208:11120/18:43916572 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/61388963:_____/18:00490321

Výsledek na webu

<a href="https://doi.org/10.1016/j.taap.2018.04.002" target="_blank" >https://doi.org/10.1016/j.taap.2018.04.002</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.taap.2018.04.002" target="_blank" >10.1016/j.taap.2018.04.002</a>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

We tested the role of substituents at the C3&apos; and C3&apos;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&apos; and C3&apos;N positions, (2) one phenyl at one of the C3&apos; and C3&apos;N positions and a non-aromatic group at the second position, (3) a non-aromatic group at both C3&apos; and C3&apos;N positions. We found that the presence of phenyl groups at both C3&apos; and C3&apos;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&apos; and C3&apos;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&apos; and C3&apos;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.

Název v anglickém jazyce

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

Popis výsledku anglicky

We tested the role of substituents at the C3&apos; and C3&apos;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&apos; and C3&apos;N positions, (2) one phenyl at one of the C3&apos; and C3&apos;N positions and a non-aromatic group at the second position, (3) a non-aromatic group at both C3&apos; and C3&apos;N positions. We found that the presence of phenyl groups at both C3&apos; and C3&apos;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&apos; and C3&apos;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&apos; and C3&apos;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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

<a href="/cs/project/LH14096" target="_blank" >LH14096: Strukturní a funkční analýza taxanových derivátů schopných překonat navozenou rezistenci ke klasickým taxanům u buněk nádorů prsu</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)<br>I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2018

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Toxicology and Applied Pharmacology

ISSN

0041-008X

e-ISSN

—

Svazek periodika

347

Číslo periodika v rámci svazku

May

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

13

Strana od-do

79-91

Kód UT WoS článku

000431165000009

EID výsledku v databázi Scopus

2-s2.0-85045191444