Antiproliferative and apoptotic activities of tosylcyclonovobiocic acids as potent heat shock protein 90 inhibitors in human cancer cells.
We evaluated whether inhibition of heat shock protein 90 (hsp90) function by novobiocin derivatives could induce the degradation of signal transducers that drive cancer cell growth and thereby promote apoptosis. Removal of the noviose moiety in novobiocin and introduction of a tosyl substituent at C-4 or C-7 coumarin nucleus provided derivatives 4TCNA and 7TCNA which compared favourably with novobiocin in MCF-7 breast cancer cells. Here we extend the antiproliferative and apoptotic properties of these analogues to a panel of cancer cell lines. Destabilization of hsp90 client proteins Raf-1, HER2, and cdk4 suggests inhibition of hsp90 chaperoning function. In HT29 colon and IGROV1 ovarian cancer cells, the growth inhibiting effect of 4TCNA and 7TCNA was consistent with the stimulation of cell death as assessed by the processing and activation of caspase 9, 8, 7 and 3 and the subsequent cleavage of poly(ADP-ribose) polymerase (PARP). In Ishikawa endometrial adenocarcinoma cells, 4TCNA also promoted apoptosis and the processing of PARP. These derivatives impacting multiple pathways involved in the neoplastic process may represent promising drugs for cancer therapy.
Radanyi
Christine
C
Université Paris Sud, CNRS, UMR 8612, Laboratoire de Pharmacologie Cellulaire et Moléculaire des Anticancéreux, Faculté de Pharmacie, IFR 141, 5 rue Jean Baptiste Clément, F-92296 Châtenay-Malabry, France. christine.radanyi@u-psud.fr
Le Bras
Gaëlle
G
Marsaud
Véronique
V
Peyrat
Jean-François
JF
Messaoudi
Samir
S
Catelli
Maria-Grazia
MG
Brion
Jean-Daniel
JD
Alami
Mouâd
M
Renoir
Jack-Michel
JM
D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D005434:Flow Cytometry; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D009675:Novobiocin / Q000737:chemistry / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D014105:Tosyl Compounds / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D061945:Caspase Inhibitors; D018841:HSP90 Heat-Shock Proteins; D014105:Tosyl Compounds; D009675:Novobiocin; D011065:Poly(ADP-ribose) Polymerases; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D020169:Caspases