Pharmacologic inhibition of CDC25 phosphatases impairs interphase microtubule dynamics and mitotic spindle assembly.
The CDC25 cell cycle regulators are promising targets for new pharmacologic approaches in cancer therapy. Inhibitory compounds such as BN82685 have proven to be effective in specifically targeting CDC25 in cultured cells and in inhibiting tumor cell growth. Here, we report that BN82685 impairs microtubule dynamic instability and alters microtubule organization and assembly at the centrosome in interphase cells. Treatment of mitotic cells with BN82685 delays mitotic spindle assembly, chromosome capture, and metaphase plate formation. Furthermore, we show that combining low concentrations of both BN82685 and paclitaxel inhibits the proliferation of HT29 human colon cancer cells. Our results show a role for CDC25 phosphatases in regulating microtubule dynamics throughout the cell cycle and suggest that combinations of CDC25 inhibitors with microtubule-targeting agents may be of therapeutic value.
Cazales
Martine
M
LBCMCP-CNRS UMR5088-IFR109, Université Paul Sabatier, 118 route de Narbonne, 31062 Toulouse, France.
Boutros
Rose
R
Brezak
Marie-Christine
MC
Chaumeron
Sophie
S
Prevost
Grégoire
G
Ducommun
Bernard
B
D016227:Benzoquinones / Q000494:pharmacology*; D002877:Chromosomes, Human / Q000187:drug effects; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D007399:Interphase / Q000187:drug effects*; D008677:Metaphase / Q000187:drug effects; D008870:Microtubules / Q000187:drug effects*; D049468:Prometaphase / Q000187:drug effects; D008941:Spindle Apparatus / Q000187:drug effects*; D013844:Thiazoles / Q000494:pharmacology*; D020687:cdc25 Phosphatases / Q000037:antagonists & inhibitors*
C506607:BN 82685; D016227:Benzoquinones; D004791:Enzyme Inhibitors; D013844:Thiazoles; D020687:cdc25 Phosphatases