Re-Establishment of a Normal Apoptotic Process as a Therapeutic Approach in B-CLL

Abstract

Even though the capacity of B-CLL leukemic cells to proliferate has been underestimated until recently, the accumulation of tumor cells in patients mostly results from a defect in the apoptotic program. Several mechanisms can account for this deficient cell death pathway. These include overexpression of anti-apoptotic molecules such as members of the Bcl-2 family, which control the opening of the mitochondrial transition permeability pore, and of the IAP (inhibitors of apoptosis) family, which inhibit the activity of caspases. The latter is also suppressed by nitric oxide (NO) released through an inducible NO synthase present in the leukemic cells. The activity of the receptors with a death domain (Fas, TRAIL) is impaired, thus contributing to the resistance to spontaneous and/or drug-induced apoptosis. Interferons as well as several cytokines and angiogenic factors are also involved in the failure of programmed cell death, either by providing efficient signals for survival (BAFF) or by counteracting the apoptotic process. A better knowledge of the mechanisms of survival and escape from apoptosis of B-CLL cells has led to the proposal of new drugs that selectively interfere at the different steps of these cascades. Their study is complicated by the lack of suitable cell lines and pre-clinical models. Nevertheless, some of these chemotherapeutic agents appear to be promising, provided they are correctly targeted to the leukemic cells.

Noxa upregulation is associated with apoptosis of chronic lymphocytic leukemia cells induced by hyperforin but not flavopiridol

“…Expression of Mcl-1 and Bcl-2 was also analyzed, as well as two proteins, which are constitutively overexpressed in CLL cells and downregulated upon flavopiridol and hyperforin-triggered apoptosis: the inducible NO synthase that produces the antiapoptotic NO, and p27kip1 that is cleaved by caspases into a p23 fragment. 4,8 Figure 1 shows that Noxa was expressed at low levels by CLL cells from eight patients (1)(2)(3)(4)(5)(6)(7)(8). In all cases, hyperforin treatment resulted in a strong increase of Noxa expression and this effect was accompanied with stimulation of PARP cleavage (and p27 cleavage in some cases), as compared to untreated controls.…”

“…On account of the low response rate of the patients to chemotherapy, new therapeutic strategies based on apoptosis inducers including plant-derived compounds are under investigation (see Kolb et al 1 …”

Targeting inhibitor of apoptosis proteins by Smac mimetic elicits cell death in poor prognostic subgroups of chronic lymphocytic leukemia

“…[3][4][5] Apoptosis represents one of the key forms of programmed cell death. 6 Necroptosis is a caspase-independent mode of programmed cell death that typically occurs when essential factors of apoptosis such as caspases are inhibited and is regulated by RIP1 and RIP3.…”

Development of Noxa-like BH3 Mimetics for Apoptosis-Based Therapeutic Strategy in Chronic Lymphocytic Leukemia

“…This accumulation of leukemic cells, which are mostly quiescent, results mainly from the inability to develop their apoptotic program (1) and an excess of survival signals delivered by the tumoral microenvironment (2). Despite recent therapeutic advances with the combination of purine analogs, alkylating agents, and monoclonal antibodies [fludarabine, cyclophosphamide, rituximab, (FCR), or allied agents; ref.…”

“…3], nearly all patients relapse, and CLL remains an incurable disease (2,3). The need to develop new strategies on the basis of apoptosis reactivation has become evident to improve treatment options for patients with CLL (1,2).…”