Resveratrol contributes to chemosensitivity of malignant mesothelioma cells with activation of p53
| Autor: | Yoon-Jin Lee, Sang-Han Lee, Ihl-Sung Park, Hae-Seon Nam, Myung-Ho Oh, Yong-Jin Lee, Jung-Hyun Shim, Moon-Kyun Cho, Ji Woong Park |
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| Rok vydání: | 2014 |
| Předmět: |
Mesothelioma
Poly ADP ribose polymerase Antineoplastic Agents Resveratrol Biology Toxicology Polymerase Chain Reaction chemistry.chemical_compound Cell Line Tumor Stilbenes Anticarcinogenic Agents Humans Cytotoxic T cell Gene silencing Fragmentation (cell biology) DNA Primers Oncogene Proteins Gene knockdown Reporter gene Base Sequence Adenine Nucleotides G1 Phase General Medicine Genes p53 Molecular biology chemistry Apoptosis Cancer research Arabinonucleosides Clofarabine Food Science |
| Zdroj: | Food and Chemical Toxicology. 63:153-160 |
| ISSN: | 0278-6915 |
| DOI: | 10.1016/j.fct.2013.11.004 |
| Popis: | Resveratrol is a naturally occurring polyphenolic phytoalexin with chemopreventive properties. We previously reported a synergistic anti-proliferative effect of resveratrol and clofarabine against malignant mesothelioma (MM) cells. Here, we further investigated molecular mechanisms involved in the synergistic interaction of these compounds in MM MSTO-211H cells. Resveratrol, in combination with clofarabine, time-dependently induced a strong cytotoxic effect with the nuclear accumulation of phospho-p53 (p-p53) in MSTO-211H cells, but not in normal mesothelial MeT-5A cells. Combination treatment up-regulated the levels of p-p53, cleaved caspase-3, and cleaved PARP proteins. Gene silencing with p53-targeting siRNA attenuated the sensitivity of cells to the combined treatment of two compounds. Analyses of p53 DNA binding assay, p53 reporter gene assay, and RTP-CR toward p53-regulated genes, including Bax, PUMA, Noxa and p21, demonstrated that induced p-p53 is transcriptionally active. These results were further confirmed by the siRNA-mediated knockdown of p53 gene. Combination treatment significantly caused the accumulation of cells at G1 phase with the increases in the sub-G0/G1 peak, DNA ladder, nuclear fragmentation, and caspase-3/7 activity. Taken together, these results demonstrate that resveratrol and clofarabine synergistically elicit apoptotic signal via a p53-dependent pathway, and provide a scientific rationale for clinical evaluation of resveratrol as a promising chemopotentiator in MM. |
| Databáze: | OpenAIRE |
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