Cell death induced by novel fluorinated taxanes in drug-sensitive and drug-resistant cancer cells.
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.
Vobořilová
Jana
J
Department of Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Ruská 87, 10000, Prague 10, Czech Republic.
Němcová-Fürstová
Vlasta
V
Neubauerová
Jitka
J
Ojima
Iwao
I
Zanardi
Ilaria
I
Gut
Ivan
I
Kovář
Jan
J
D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D004273:DNA, Neoplasm / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D017611:Fluorine Compounds / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D017239:Paclitaxel / Q000737:chemistry / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D043823:Taxoids / Q000737:chemistry / Q000494:pharmacology*
D004273:DNA, Neoplasm; D017611:Fluorine Compounds; D017382:Reactive Oxygen Species; D043823:Taxoids; D045304:Cytochromes c; D020169:Caspases; D017239:Paclitaxel