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

Abstract

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 apoptosisinducing 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.

Suberoylanilide hydroxamic acid sensitizes human oral cancer cells to TRAIL-induced apoptosis through increase DR5 expression

“…In oral cancer cells, p53 is frequently inactivated. In some cell types, DR5 is a downstream target of p53 (32,33). Some conventional chemotherapeutic drugs, including etoposide or doxorubicin, can induce DR5 expression and enhance TRAILinduced apoptosis in a p53-dependent manner in certain cancer cell types such as lung cancer and lymphocytic leukemia cells (32,33).…”

On the TRAIL of a new therapy for leukemia

“…88,107,108 There was initially hope that treatment of CLL cells with TRAIL might by itself induce apoptosis. Previous studies, however, not only demonstrated that CLL cells are resistant to the induction of apoptosis by TRAIL, 88,107 but also suggested that recruitment of FADD and cleavage of caspase 8 is low in CLL isolates compared to the Jurkat T-cell leukemia line.…”

“…88,107,108 There was initially hope that treatment of CLL cells with TRAIL might by itself induce apoptosis. Previous studies, however, not only demonstrated that CLL cells are resistant to the induction of apoptosis by TRAIL, 88,107 but also suggested that recruitment of FADD and cleavage of caspase 8 is low in CLL isolates compared to the Jurkat T-cell leukemia line. 107 In a subsequent study, MacFarlane and co-workers also showed that the HDAC inhibitors depsipeptide and trichostatin A, two examples of a promising new class of anticancer agents undergoing extensive preclinical and clinical investigation, [109][110][111][112] are unable to induce apoptosis in CLL cells by themselves, but nonetheless sensitize CLL cells to TRAIL.…”

“…[80][81][82] Moreover, the balance among these receptors is dynamic rather than static. 83 For example, DR5, which has previously been identified as the more prominent receptor involved in TRAILinduced killing of tumor cells, 84,85 is upregulated in a p53-dependent manner after DNA damage, [86][87][88] providing at least a partial explanation for the ability of DNA-damaging anticancer drugs to synergize with TRAIL in vitro and in vivo. 69,71,[87][88][89] There are other levels of regulation as well.…”

“…83 For example, DR5, which has previously been identified as the more prominent receptor involved in TRAILinduced killing of tumor cells, 84,85 is upregulated in a p53-dependent manner after DNA damage, [86][87][88] providing at least a partial explanation for the ability of DNA-damaging anticancer drugs to synergize with TRAIL in vitro and in vivo. 69,71,[87][88][89] There are other levels of regulation as well. As noted above, the recruitment of FADD by ligated death receptors 37,38 and the recruitment/activation of caspase 8 by FADD [30][31][32][33] appear to be regulated processes.…”