PARP inhibition sensitizes p53-deficient breast cancer cells to doxorubicin-induced apoptosis
| Autor: | J M Ruiz de Almodóvar, F. Javier Oliver, Ana Cañuelo, José Antonio Muñoz-Gámez, Gilbert de Murcia, David Martín-Oliva, Rocío Aguilar-Quesada, M. Isabel Núñez, M. Teresa Valenzuela |
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| Přispěvatelé: | Cancérogenèse et mutagenèse moléculaire et structurale (CMMS), Centre National de la Recherche Scientifique (CNRS), Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2005 |
| Předmět: |
MESH: Neoplasm Proteins
Poly (ADP-Ribose) Polymerase-1 MESH: Genes p53 Apoptosis MESH: Poly (ADP-Ribose) Polymerase-1 Quinolones Biochemistry Poly (ADP-Ribose) Polymerase Inhibitor MESH: Drug Synergism Membrane Potentials MESH: Caspase 3 Tumor Cells Cultured Cytotoxic T cell MESH: Tumor Suppressor Protein p53 Tumor Stem Cell Assay bcl-2-Associated X Protein biology Caspase 3 MESH: Tumor Stem Cell Assay Drug Synergism MESH: 1-Naphthylamine MESH: Drug Resistance Neoplasm Mitochondria Neoplasm Proteins Naphthalimides MESH: Intracellular Membranes [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry Molecular Biology/Biomolecules [q-bio.BM] 1-Naphthylamine MESH: Naphthalimides Proto-Oncogene Proteins c-bcl-2 Caspases Female Poly(ADP-ribose) Polymerases medicine.drug Research Article DNA damage MESH: Mitochondria Poly ADP ribose polymerase Breast Neoplasms Poly(ADP-ribose) Polymerase Inhibitors MESH: Poly(ADP-ribose) Polymerase Inhibitors MESH: Doxorubicin Bcl-2-associated X protein medicine Humans MESH: Membrane Potentials Doxorubicin MESH: bcl-2-Associated X Protein [SDV.BBM]Life Sciences [q-bio]/Biochemistry Molecular Biology MESH: Tumor Cells Cultured Molecular Biology MESH: Humans MESH: Quinolones MESH: Caspases MESH: Apoptosis MESH: Poly(ADP-ribose) Polymerases Cell Biology Intracellular Membranes Genes p53 Molecular biology body regions MESH: Proto-Oncogene Proteins c-bcl-2 Drug Resistance Neoplasm biology.protein Cancer research Tumor Suppressor Protein p53 MESH: Female MESH: Breast Neoplasms |
| Zdroj: | Biochemical Journal Biochemical Journal, Portland Press, 2005, 386 (Pt 1), pp.119-25. ⟨10.1042/BJ20040776⟩ |
| ISSN: | 0264-6021 1470-8728 |
| DOI: | 10.1042/BJ20040776⟩ |
| Popis: | p53 deficiency confers resistance to doxo (doxorubicin), a clinically active and widely used antitumour anthracycline antibiotic. The purpose of the present study was to investigate the reversal mechanism of doxo resistance by the potent PARP [poly(ADP-ribose) polymerase] inhibitor ANI (4-amino-1,8-naphthalimide) in the p53-deficient breast cancer cell lines EVSA-T and MDA-MB-231. The effects of ANI, in comparison with doxo alone, on doxo-induced apoptosis, were investigated in matched pairs of EVSA-T or MDA-MB-231 with or without ANI co-treatment. Doxo elicited PARP activation as determined by Western blotting and immunofluorescence of poly(ADP-ribose), and ANI enhanced the cytotoxic activity of doxo 2.3 times and in a caspase-dependent manner. The long-term cytotoxic effect was studied by a colony-forming assay. Using this assay, ANI also significantly potentiates the long-term cytotoxic effect with respect to treatment with doxo alone. Decrease in mitochondrial potential together with an increase in cytochrome c release, association of Bax with the mitochondria and caspase 3 activation were also observed in the presence of ANI. Therefore PARP inhibition may represent a novel way of selectively targeting p53-deficient breast cancer cells. The underlying mechanism is probably a potentiation of unrepaired DNA damage, shifting from DNA repair to apoptosis due to the effective inhibition of PARP activity. |
| Databáze: | OpenAIRE |
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