Role of the TRAIL/APO2-L death receptors in chlorambucil- and fludarabine-induced apoptosis in chronic lymphocytic leukemia

被引:50
作者
Johnston, JB
Kabore, AF
Strutinsky, J
Hu, XJ
Paul, JT
Kropp, DM
Kuschak, B
Begleiter, A
Gibson, SB
机构
[1] Univ Manitoba, Manitoba Inst Cell Biol, Winnipeg, MB R3E 0V9, Canada
[2] Univ Manitoba, Dept Biochem & Med Genet, Winnipeg, MB R3E 0V9, Canada
[3] Univ Manitoba, Dept Pharmacol & Therapeut, Winnipeg, MB, Canada
[4] Univ Manitoba, Dept Internal Med, Winnipeg, MB R3E 0V9, Canada
关键词
apoptosis; death receptors; chronic lymphocytic leukemia; TRAIL; chemotherapeutic drugs;
D O I
10.1038/sj.onc.1207004
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The standard treatments for chronic lymphocytic leukemia (CLL) include the alkylating agent chlorambucil (CLB) and the nucleoside analog fludarabine (F-ara-AMP, Flu). Tumor necrosis factor-related apoptosis-inducing ligand ( TRAIL) is a death receptor ligand that induces apoptosis preferentially in tumors. However, CLL cells seem to be resistant to TRAIL-induced apoptosis. The TRAIL apoptotic signaling pathway has also been implicated in genotoxin-induced apoptosis through upregulation of TRAIL death receptors DR4 and DR5. In the present study, we demonstrate that the treatment of primary CLL cells with CLB or Flu increases the mRNA, protein and cell surface expression levels of DR4 and DR5 in a dose-dependent manner. In contrast to CLL cells, drug treatment fails to increase significantly the expression of DR4 or DR5 in normal lymphocytes. CLL cells are, however, resistant to TRAIL-induced apoptosis compared to B-cell lines. In contrast, combinational treatment using CLB or Flu with TRAIL (100 ng/ml) gave a synergistic apoptotic response. Furthermore, TRAIL is readily detectable on the cell surface of CLL cells, but TRAIL expression fails to increase following drug treatment. Preventing TRAIL from interacting with DR4 and DR5 decreases CLB-induced apoptosis in CLL cells. A similar, but less marked effect is observed with Flu. These findings indicate the involvement of the TRAIL apoptotic pathway in the mechanism of action of chemotherapy, and this mechanism could be utilized to sensitize CLL cells to TRAIL-induced apoptosis.
引用
收藏
页码:8356 / 8369
页数:14
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