The aim of this study is to compare the effects of new fluorinated taxanes SB-T-12851, SB-T-12852, SB-T-12853, and SB-T-12854 with those of the classical taxane paclitaxel and novel non-fluorinated taxane SB-T-1216 on cancer cells. Paclitaxel-sensitive MDA-MB-435 and paclitaxel-resistant NCI/ADR-RES human cancer cell lines were used. Cell growth and survival evaluation, colorimetric assessment of caspases activities, flow cytometric analyses of the cell cycle and the assessment of mitochondrial membrane potential, reactive oxygen species (ROS) and the release of cytochrome c from mitochondria were employed. Fluorinated taxanes have similar effects on cell growth and survival. For MDA-MB-435 cells, the C(50) of SB-T-12851, SB-T-12852, SB-T-12853 and SB-T-12854 was 3 nM, 4 nM, 3 nM and 5 nM, respectively. For NCI/ADR-RES cells, the C(50) of SB-T-12851, SB-T-12852, SB-T-12853, and SB-T-12854 was 20 nM, 20 nM, 10 nM and 10 nM, respectively. Selected fluorinated taxanes, SB-T-12853 and SB-T-12854, at the death-inducing concentrations (30 nM for MDA-MB-435 and 300 nM for NCI/ADR-RES) were shown to activate significantly caspase-3, caspase-9, caspase-2 and also slightly caspase-8. Cell death was associated with significant accumulation of cells in the G(2)/M phase. Cytochrome c was not released from mitochondria and other mitochondrial functions were not significantly impaired. The new fluorinated taxanes appear to use the same or similar mechanisms of cell death induction as compared with SB-T-1216 and paclitaxel. New fluorinated and non-fluorinated taxanes are more effective against drug-resistant cancer cells than paclitaxel. Therefore, new generation of taxanes, either non-fluorinated or fluorinated, are excellent candidates for further and detailed studies.
- MeSH
- buněčná smrt účinky léků MeSH
- buněčný cyklus účinky léků MeSH
- chemorezistence účinky léků MeSH
- cytochromy c sekrece MeSH
- DNA nádorová metabolismus MeSH
- kaspasy metabolismus MeSH
- léky antitumorózní - screeningové testy MeSH
- lidé MeSH
- mitochondrie účinky léků metabolismus MeSH
- nádorové buněčné linie MeSH
- paclitaxel chemie farmakologie MeSH
- proliferace buněk účinky léků MeSH
- reaktivní formy kyslíku metabolismus MeSH
- sloučeniny fluoru chemie farmakologie MeSH
- taxoidy chemie farmakologie MeSH
- viabilita buněk účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Three types of 5alpha-androstane and ergostane analogues of brassinolide, containing a fluorine atom in either the 3alpha or the 5alpha positions or in 3alpha and 5alpha positions, were prepared using standard operations (reaction of 3beta-alcohols with (diethylamino)sulfur trifluoride, cleavage of epoxide with HF in py or BF 3.Et 2O). The 5alpha-fluorine was found to affect chemical reactivity (e.g., electrophilic addition to the Delta (2)-double bond) as well as physical properties (e.g., NMR, chromatographic behavior) of the products. Cytotoxicity of the products was studied using human normal and cancer cell lines with 28-homocastasterone as positive control and their brassinolide type activity was established using the bean second-internode test with 24-epibrassinolide as standard. The equivalence of F and OH groups was observed in some of the active compounds. The anticancer and the brassinolide-type activity do not correlate with each other: ergostane derivatives were most active in the former test while androstane derivatives were best in the latter.
- MeSH
- antitumorózní látky farmakologie chemická syntéza chemie MeSH
- buněčné linie MeSH
- cholestanoly farmakologie chemická syntéza chemie MeSH
- financování organizované MeSH
- lidé MeSH
- molekulární struktura MeSH
- sloučeniny fluoru farmakologie chemická syntéza chemie MeSH
- steroidy heterocyklické farmakologie chemická syntéza chemie MeSH
- viabilita buněk účinky léků MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- MeSH
- lidé MeSH
- sloučeniny fluoru farmakologie MeSH
- zubní kaz farmakoterapie prevence a kontrola MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- kongresy MeSH
