Synergistic antitumor effects of novel HDAC inhibitors and paclitaxel in vitro and in vivo

Autor: Franco Zunino, Raffaella Nannei, Raffaella Cincinelli, Claudio Pisano, Michelandrea De Cesare, Valentina Zuco, Nadia Zaffaroni
Jazyk: angličtina
Rok vydání: 2011
Předmět:
Cancer Treatment
Gene Expression
lcsh:Medicine
Apoptosis
Pharmacology
Microtubules
Polymerization
chemistry.chemical_compound
Mice
Tubulin
Antineoplastic Combined Chemotherapy Protocols
Molecular Cell Biology
lcsh:Science
Multidisciplinary
biology
Cell Death
Nocodazole
Cell Cycle
Acetylation
Drug Synergism
Vinorelbine
Histone Modification
Cell cycle
Vinblastine
Mitochondria
Ovarian Cancer
Paclitaxel
Oncology
Medicine
Female
Epigenetics
medicine.drug
Research Article
Cyclin-Dependent Kinase Inhibitor p21
Antineoplastic Agents
Epigenetic Therapy
In vivo
Cell Line
Tumor
medicine
Genetics
Animals
Humans
Cell Shape
Biology
Cell Proliferation
Cell growth
lcsh:R
Cancers and Neoplasms
Chemotherapy and Drug Treatment
Xenograft Model Antitumor Assays
In vitro
Histone Deacetylase Inhibitors
chemistry
biology.protein
lcsh:Q
Tumor Suppressor Protein p53
Gynecological Tumors
Zdroj: PLoS ONE, Vol 6, Iss 12, p e29085 (2011)
PLoS ONE
ISSN: 1932-6203
Popis: Preclinical studies support the therapeutic potential of histone deacetylases inhibitors (HDACi) in combination with taxanes. The efficacy of combination has been mainly ascribed to a cooperative effect on microtubule stabilization following tubulin acetylation. In the present study we investigated the effect of paclitaxel in combination with two novel HDACi, ST2782 or ST3595, able to induce p53 and tubulin hyperacetylation. A synergistic effect of the paclitaxel/ST2782 (or ST3595) combination was found in wild-type p53 ovarian carcinoma cells, but not in a p53 mutant subline, in spite of a marked tubulin acetylation. Such a synergistic interaction was confirmed in additional human solid tumor cell lines harboring wild-type p53 but not in those expressing mutant or null p53. In addition, a synergistic cytotoxic effect was found when ST2782 was combined with the depolymerising agent vinorelbine. In contrast to SAHA, which was substantially less effective in sensitizing cells to paclitaxel-induced apoptosis, ST2782 prevented up-regulation of p21(WAF1/Cip1) by paclitaxel, which has a protective role in response to taxanes, and caused p53 down-regulation, acetylation and mitochondrial localization of acetylated p53. The synergistic antitumor effects of the paclitaxel/ST3595 combination were confirmed in two tumor xenograft models. Our results support the relevance of p53 modulation as a major determinant of the synergistic interaction observed between paclitaxel and novel HDACi and emphasize the therapeutic interest of this combination.
Databáze: OpenAIRE
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