Abstract |
Mcl-1 and Bcl-xL, key anti-apoptotic proteins of the Bcl-2 family, have attracted attention as important molecules in the cell survival and drug resistance. In this study, we investigated whether inhibition of Bcl-xL influences cell growth and apoptosis against simultaneous treatment of resveratrol and clofarabine in the human malignant mesothelioma H-2452 cells. Resveratrol and clofarabine decreased Mcl-1 protein levels but had little effect on Bcl-xL levels. In the presence of two compounds, any detectable change in the Mcl-1 mRNA levels was not observed in RT-PCR analysis, whereas pretreatment with the proteasome inhibitor MG132 led to its accumulation to levels far above basal levels. The knockdown of Bcl-xL inhibited cell proliferation with cell accumulation at G2/M phase and the appearance of sub-G0/G1 peak in DNA flow cytometric assay. The suppression of cell growth was accompanied by an increase in the caspase-3/7 activity with the resultant cleavages of procaspase-3 and its substrate poly (ADP-ribose) polymerase, and increased percentage of apoptotic propensities in annexin V binding assay. Collectively, our data represent that the efficacy of resveratrol and clofarabine for apoptosis induction was substantially enhanced by Bcl-xL-lowering strategy in which the simultaneous targeting of Mcl-1 and Bcl-xL could be a more effective strategy for treating malignant mesothelioma.
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Authors | Yoon-Jin Lee, In-Sung Hwang, Yong-Jin Lee, Chang-Ho Lee, Sung-Ho Kim, Hae-Saeon Nam, Young-Jin Choi, Sang-Han Lee |
Journal | Journal of Korean medical science
(J Korean Med Sci)
Vol. 29
Issue 11
Pg. 1464-72
(Nov 2014)
ISSN: 1598-6357 [Electronic] Korea (South) |
PMID | 25408576
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Adenine Nucleotides
- Antimetabolites, Antineoplastic
- Arabinonucleosides
- Leupeptins
- MCL1 protein, human
- Myeloid Cell Leukemia Sequence 1 Protein
- RNA, Messenger
- RNA, Small Interfering
- Stilbenes
- bcl-X Protein
- Clofarabine
- Caspase 3
- Caspase 7
- Resveratrol
- benzyloxycarbonylleucyl-leucyl-leucine aldehyde
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Topics |
- Adenine Nucleotides
(pharmacology)
- Antimetabolites, Antineoplastic
(pharmacology)
- Apoptosis
(drug effects)
- Arabinonucleosides
(pharmacology)
- Caspase 3
(metabolism)
- Caspase 7
(metabolism)
- Cell Line, Tumor
- Cell Proliferation
(drug effects)
- Clofarabine
- G2 Phase Cell Cycle Checkpoints
(drug effects)
- Gene Knockdown Techniques
- Humans
- Leupeptins
(pharmacology)
- Lung Neoplasms
(metabolism, pathology)
- M Phase Cell Cycle Checkpoints
(drug effects)
- Mesothelioma
(metabolism, pathology)
- Mesothelioma, Malignant
- Myeloid Cell Leukemia Sequence 1 Protein
(antagonists & inhibitors, genetics, metabolism)
- RNA Interference
- RNA, Messenger
(metabolism)
- RNA, Small Interfering
(metabolism)
- Resveratrol
- Stilbenes
(pharmacology)
- bcl-X Protein
(antagonists & inhibitors, genetics, metabolism)
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