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Prepublished online as a Blood First Edition Paper on November 21, 2002; DOI 10.1182/blood-2002-07-1984.
Submitted July 3, 2002
Accepted November 13, 2002
The vitamin D3 analog, EB1089, induces apoptosis via a p53-independent mechanism involving p38 MAP kinase activation and suppression of ERK activity in B-cell chronic lymphocytic leukemia cells in vitro
Chris Pepper*, Alun Thomas, Terry Hoy, Donald Milligan, Paul Bentley, and Chris Fegan
Department of Haematology, Llandough Hospital, Penarth, United Kingdom
Department of Haematology, University of Wales, College of Medicine, Cardiff, United Kingdom
Department of Haematology, Birmingham Heartlands Hospital, Birmingham, United Kingdom
* Corresponding author; email: chrisp{at}llanhaem.demon.co.uk.
EB1089, a novel vitamin D3 analog, has been shown to have cytotoxic and anti-proliferative properties in a variety of malignant cells. However, its potential as a treatment for B-cell chronic lymphocytic leukemia (B-CLL) has not been evaluated. EB1089 induced apoptosis in all of the 102 B-CLL samples tested with a mean LD50 value (±SD) of 2.1 (± 1.4) x 10-8 M. Furthermore, no significant difference was found in the cytotoxicity of EB1089 in B-CLL samples from previously treated and untreated patients (p = 0.1637). Induction of apoptosis was associated with a reduction in Bcl-2 and Mcl-1 protein expression but this was only evident in the apoptotic cells. In contrast, the expression of Bax, p21 and p53 were not altered in the viable or apoptotic cells from either B- or T-lymphocyte lineages. EB1089-induced apoptosis was preceded by activation of p38 MAP kinase and suppression of ERK activity and this was associated with downstream activation of caspase-3. The pan-caspase inhibitor (Z-VAD-FMK) and the caspase-9 inhibitor (Z-LEHD-FMK) were able to partially abrogate the apoptotic effects of EB1089 but did not affect the phosphorylation of p38 MAP kinase or the suppression of ERK. The B-CLL cells in the study were shown to highly express vitamin D receptor but an additional receptor-independent mechanism of cell killing cannot be ruled out at this stage. These findings show that EB1089 is a potent apoptosis-inducing agent in B-CLL cells and may be useful in the treatment of B-CLL patients particularly those with p53 mutations or drug resistant disease.
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