Antiproliferative and apoptotic activities of tosylcyclonovobiocic acids as potent heat shock protein 90 inhibitors in human cancer cells
| Autor: | Véronique Marsaud, Jean-Daniel Brion, Samir Messaoudi, Gaëlle Le Bras, Jean-François Peyrat, Mouâd Alami, C Radanyi, Maria-Grazia Catelli, Jack-Michel Renoir |
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| Rok vydání: | 2009 |
| Předmět: |
Cancer Research
Programmed cell death Poly ADP ribose polymerase Blotting Western Apoptosis Biology Tosyl Compounds Neoplasms Heat shock protein Tumor Cells Cultured medicine Humans HSP90 Heat-Shock Proteins Novobiocin Cell Proliferation Cell growth Cell Cycle Cyclin-Dependent Kinase 4 Cell cycle Flow Cytometry Caspase Inhibitors Oncology Caspases Cancer cell Cancer research Poly(ADP-ribose) Polymerases medicine.drug |
| Zdroj: | Cancer Letters. 274:88-94 |
| ISSN: | 0304-3835 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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