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Prepublished online as a Blood First Edition Paper on November 21, 2002; DOI 10.1182/blood-2002-07-1984.
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Blood, 1 April 2003, Vol. 101, No. 7, pp. 2454-2459
PLENARY PAPER
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
From the Departments of Haematology, Llandough
Hospital, Penarth, Vale of Glamorgan; University of Wales College of
Medicine, Cardiff; and Birmingham Heartlands Hospital, United
Kingdom.
EB1089, a novel vitamin D3 analog, has been shown to have cytotoxic
and antiproliferative 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 (the
concentration of EB1089 required to kill 50% of cells) value (± SD)
of 2.1 × 10 8 M (± 1.4 × 108 M).
Furthermore, no significant difference was found in the cytotoxicity of
EB1089 in B-CLL samples from previously treated and untreated patients
(P = .1637). Induction of apoptosis was associated with a
reduction in Bcl-2 and Mcl-1 protein expression, but this was evident
only in the apoptotic cells. In contrast, the expression of Bax, p21,
and p53 was not altered in the viable or apoptotic cells from either B-
or T-lymphocyte lineages. EB1089-induced apoptosis was preceded by
activation of p38 mitogen-activated protein (MAP) kinase and
suppression of extracellular signal-regulated kinase (ERK) activity,
and this was associated with downstream activation of caspase-3. The
pancaspase 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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