The BH3 mimetic compound, ABT-737, synergizes with a range of cytotoxic chemotherapy agents in chronic lymphocytic leukemia

Abstract

As chronic lymphocytic leukemia (CLL) is characterized by overexpression of pro-survival BCL2, compounds that mimic its physiological antagonists, the BH3-only proteins, may have a role in treatment of this disease. ABT-737 is a BH3 mimetic compound that selectively targets BCL2 and BCLX L . In the present work, we report that ABT-737 is highly effective (LC 50 o50 nM) as a single agent against most (21/30) primary CLL samples, but that a sizable minority is relatively insensitive. In vitro sensitivity to ABT-737 could not be simply predicted by the patients' clinical features, including response to prior therapy or known prognostic markers (CD38 expression, 17p deletion), or the relative expression of BCL2 family proteins (BCL2, MCL1, BAX, BIM). Strikingly, co-incubation with cytotoxic agents (dexamethasone, etoposide, fludarabine, doxorubicin) sensitized most CLL samples to ABT-737, but this could not be predicted by responses to either ABT-737 or the cytotoxic agent alone. Of 17 samples least sensitive to ABT-737, 13 were sensitized by co-treatment with at least one cytotoxic agent. These data indicate that combination of ABT-737 with a second anti-leukemic agent would improve response rates and suggest a potential role for combination therapies that include BH3 mimetics for the treatment of this disease.

Histone deacetylase inhibitors are unable to synergize with ABT-737 in killing primary chronic lymphocytic leukaemia cells in vitro

“…The lack of a significant response to vorinostat or panobinostat alone (Figure 1b): (i) was consistent with the observed high levels of expression of BCL-2 in our CLL samples ( Figure 1c); (ii) was not due to inactivity of HDACi in the CLL cells since western blotting demonstrated a clear time-dependent increase in histone H3 acetylation following exposure to vorinostat ( Figure 1d); (iii) was consistent with our previous results for murine lymphoma cells overexpressing BCL-2. 1 As ABT-737 alone ( Figure 1e) exhibited a range in potency towards CLL comparable to reported results from others, 4 we surmised that the lack of synergy between the HDACi and ABT-737 may be due to a defect in the ability of HDACi to promote apoptotic signalling upstream of BCL-2.…”

“…Expression levels for BMF and H1F0 were normalised by comparison with expression of the 60S ribosomal protein L32, which does not change in response to HDAC inhibitors. 4 Fold change was calculated relative to the 0 hr time point. Primer sequences used were: L32, 5 0 -TTC CTG GTC CAC AAC GTC AAG-3 0 and 5 0 -TTG TGA GCG ATC TCG GCA C-3 0 ; BMF, 5 0 -CAG GAA GAC AAA GCT ACC CAG ACT-3 0 and 5 0 -GCC GAT AGC CAG CAT TGC CAT AAA-3 0 ; H1F0, 5 0 -ATC TTT GTG GCT TCA GCA AAT TCT-3 0 and 5 0 -AAG TTT CAA CAG GGC ACA CTG AG-3 0 .…”

The BCL-2 protein family, BH3-mimetics and cancer therapy

“…Indeed BH3-mimetics have been found to potently synergise in vitro with various chemotherapeutic drugs in the killing of CLL 165 and many other cancer cells, including mouse xenograft models of human breast cancer. 152,153,157,166,167 Such combinatorial therapeutic strategies would effectively neutralise all pro-survival BCL-2 family proteins and thereby efficiently activate apoptosis in malignant cells.…”

p53 and Notch signaling in chronic lymphocytic leukemia: clues to identifying novel therapeutic strategies

“…ABT 737, a 'BH3-mimetic' drug designed to neutralize the antiapoptotic function of Bcl-2 and related proteins, induces apoptosis of CLL cells at low nanomolar concentrations, [70][71][72][73] and also synergizes with a range of conventional cytotoxic agents 72 and with proteasome inhibitors. 73 It is likely that this drug and its derivatives will bypass p53 and therefore retain toxicity toward p53 dysfunctional CLL cells.…”