Inhibition of human tumor cell growth in vivo by an orally bioavailable inhibitor of CDC25 phosphatases.
Cell cycle regulators, such as the CDC25 phosphatases, are potential targets for the development of new anticancer drugs. Here we report the identification and the characterization of BN82685, a quinone-based CDC25 inhibitor that is active in vitro and in vivo. BN82685 inhibits recombinant CDC25A, B, and C phosphatases in vitro. It inhibits the growth of human tumor cell lines with an IC(50) in the submicromolar range, independently of their resistance to chemotherapeutic agents. This inhibitory effect is irreversible on both the purified CDC25 enzyme in vitro and on tumor cell proliferation. The specificity of BN82685 towards the CDC25 phosphatases is shown by an increase in cyclin-dependent kinase 1 tyrosine 15 phosphorylation, by the reversion of the mitosis-inducing effect of CDC25B overexpression in HeLa cells, and by the lack of a growth inhibitory effect in an assay based on the use of a CDC25-independent fission yeast model. Finally, when administered p.o., BN82685 is shown to inhibit the growth of the human pancreatic tumor Mia PaCa-2 xenografted in athymic nude mice. BN82685 is therefore a promising new compound targeting CDC25, which confirms the interest of the inhibition of these enzymes as an anticancer therapeutic strategy.
Brezak
Marie-Christine
MC
IPSEN, Institut Henri Beaufour, Les Ulis, France.
Quaranta
Muriel
M
Contour-Galcera
Marie-Odile
MO
Lavergne
Olivier
O
Mondesert
Odile
O
Auvray
Pierrïck
P
Kasprzyk
Philip G
PG
Prevost
Gregoire P
GP
Ducommun
Bernard
B
D000284:Administration, Oral; D000818:Animals; D016227:Benzoquinones / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D001682:Biological Availability; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008938:Mitosis / Q000187:drug effects; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000473:pathology*; D012568:Schizosaccharomyces / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D013844:Thiazoles / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D023041:Xenograft Model Antitumor Assays; D020687:cdc25 Phosphatases / Q000037:antagonists & inhibitors*
C506607:BN 82685; D016227:Benzoquinones; D004791:Enzyme Inhibitors; D013844:Thiazoles; D020687:cdc25 Phosphatases