Knockdown of Bcl-xL Enhances Growth-Inhibiting and Apoptosis-Inducing Effects of Resveratrol and Clofarabine in Malignant Mesothelioma H-2452 Cells.
10.3346/jkms.2014.29.11.1464
- Author:
Yoon Jin LEE
1
;
In Sung HWANG
;
Yong Jin LEE
;
Chang Ho LEE
;
Sung Ho KIM
;
Hae Saeon NAM
;
Young Jin CHOI
;
Sang Han LEE
Author Information
1. Soonchunhyung Environmental Health Center for Asbestos, Soonchunhyang University Cheonan Hospital, Cheonan, Korea. m1037624@sch.ac.kr
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords:
Mesothelioma, Malignant;
Mcl-1;
Bcl-xL;
Resveratol;
Clofarabine;
Apoptosis
- MeSH:
Adenine Nucleotides/*pharmacology;
Antimetabolites, Antineoplastic/*pharmacology;
Apoptosis/*drug effects;
Arabinonucleosides/*pharmacology;
Caspase 3/metabolism;
Caspase 7/metabolism;
Cell Line, Tumor;
Cell Proliferation/drug effects;
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;
Myeloid Cell Leukemia Sequence 1 Protein/antagonists & inhibitors/genetics/metabolism;
RNA Interference;
RNA, Messenger/metabolism;
RNA, Small Interfering/metabolism;
Stilbenes/*pharmacology;
bcl-X Protein/antagonists & inhibitors/*genetics/*metabolism
- From:Journal of Korean Medical Science
2014;29(11):1464-1472
- CountryRepublic of Korea
- Language:English
-
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.
