Resveratrol contributes to chemosensitivity of malignant mesothelioma cells with activation of p53
- Abstract
- 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.
- All Author(s)
- Y. J. Lee
; I. S. Park
; J. H. Shim
; M. K. Cho
; H. S. Nam
; J. W. Park
; M. H. Oh
; S. H. Lee
- Issued Date
- 2014
- Type
- Article
- Keyword
- Resveratrol; Clofarabine; Mesothelioma; Apoptosis; p53; Chemopotentiator
- Publisher
- British Industrial Biological Research Association
- ISSN
- 0278-6915
- Citation Title
- Food and Chemical Toxicology
- Citation Volume
- 63
- Citation Start Page
- 153
- Citation End Page
- 160
- Language(ISO)
- eng
- DOI
- 10.1016/j.fct.2013.11.004
- URI
- http://schca-ir.schmc.ac.kr/handle/2022.oak/2664
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