We tested the effect of substituents at the (1) C3´, C3´N, (2) C10, and (3) C2-meta-benzoate positions of taxane derivatives on their activity against sensitive versus counterpart paclitaxel-resistant breast (MCF-7) and ovarian (SK-OV-3) cancer cells. We found that (1) non-aromatic groups at both C3´ and C3´N positions, when compared with phenyl groups at the same positions of a taxane derivative, significantly reduced the resistance of ABCB1 expressing MCF-7/PacR and SK-OV-3/PacR cancer cells. This is, at least in the case of the SB-T-1216 series, accompanied by an ineffective decrease of intracellular levels in MCF-7/PacR cells. The low binding affinity of SB-T-1216 in the ABCB1 binding cavity can elucidate these effects. (2) Cyclopropanecarbonyl group at the C10 position, when compared with the H atom, seems to increase the potency and capability of the derivative in overcoming paclitaxel resistance in both models. (3) Derivatives with fluorine and methyl substituents at the C2-meta-benzoate position were variously potent against sensitive and resistant cancer cells. All C2 derivatives were less capable of overcoming acquired resistance to paclitaxel in vitro than non-substituted analogs. Notably, fluorine derivatives SB-T-121205 and 121,206 were more potent against sensitive and resistant SK-OV-3 cells, and derivatives SB-T-121405 and 121,406 were more potent against sensitive and resistant MCF-7 cells. (4) The various structure-activity relationships of SB-T derivatives observed in two cell line models known to express ABCB1 favor their complex interaction not based solely on ABCB1.

• Klíčová slova
• C10 taxane derivatives, C2 taxane derivatives, C3´ and C3´N taxane derivatives, Resistant breast cancer cells, Resistant ovarian cancer cells,
• MeSH
• benzoáty farmakologie   chemie   MeSH
• chemorezistence * účinky léků   MeSH
• lidé MeSH
• MFC-7 buňky MeSH
• nádorové buněčné linie MeSH
• nádory prsu farmakoterapie   patologie   MeSH
• nádory vaječníků farmakoterapie   patologie   MeSH
• P-glykoproteiny * metabolismus   genetika   MeSH
• paclitaxel farmakologie   MeSH
• protinádorové látky farmakologie   chemie   MeSH
• taxoidy farmakologie   chemie   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• ABCB1 protein, human MeSH Prohlížeč
• benzoáty MeSH
• P-glykoproteiny * MeSH
• paclitaxel MeSH
• protinádorové látky MeSH
• taxoidy MeSH

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.

• Klíčová slova
• ABCB1 transporter, Acquired resistance to paclitaxel, Breast cancer cells, Molecular docking, Taxane derivates,
• MeSH
• biologický transport MeSH
• chemorezistence * genetika   MeSH
• fytogenní protinádorové látky chemie   metabolismus   farmakologie   MeSH
• lidé MeSH
• MFC-7 buňky MeSH
• molekulární struktura MeSH
• nádory prsu farmakoterapie   genetika   metabolismus   patologie   MeSH
• P-glykoproteiny genetika   metabolismus   MeSH
• paclitaxel chemie   metabolismus   farmakologie   MeSH
• proliferace buněk účinky léků   MeSH
• simulace molekulového dockingu MeSH
• vazba proteinů MeSH
• viabilita buněk účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• srovnávací studie MeSH
• Názvy látek
• ABCB1 protein, human MeSH Prohlížeč
• fytogenní protinádorové látky MeSH
• P-glykoproteiny MeSH
• paclitaxel MeSH

Microtubule drugs such as paclitaxel, colchicine, vinblastine, trifluralin, or oryzalin form a chemically diverse group that has been reinforced by a large number of novel compounds over time. They all share the ability to change microtubule properties. The profound effects of disrupted microtubule systems on cell physiology can be used in research as well as anticancer treatment and agricultural weed control. The activity of microtubule drugs generally depends on their binding to α- and β-tubulin subunits. The microtubule drugs are often effective only in certain taxonomic groups, while other organisms remain resistant. Available information on the molecular basis of this selectivity is summarized. In addition to reviewing published data, we performed sequence data mining, searching for kingdom-specific signatures in plant, animal, fungal, and protozoan tubulin sequences. Our findings clearly correlate with known microtubule drug resistance determinants and add more amino acid positions with a putative effect on drug-tubulin interaction. The issue of microtubule network properties in plant cells producing microtubule drugs is also addressed.

• MeSH
• druhová specificita MeSH
• houby MeSH
• lidé MeSH
• mikrotubuly účinky léků   metabolismus   MeSH
• modulátory tubulinu farmakologie   MeSH
• rostliny MeSH
• taxoidy farmakologie   MeSH
• tubulin účinky léků   genetika   fyziologie   MeSH
• vinca alkaloidy farmakologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• modulátory tubulinu MeSH
• taxoidy MeSH
• tubulin MeSH
• vinca alkaloidy MeSH