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Blood, Vol. 92 No. 10 (November 15), 1998:
pp. 3804-3816
Flavopiridol Induces Apoptosis in Chronic Lymphocytic Leukemia
Cells Via Activation of Caspase-3 Without Evidence of bcl-2
Modulation or Dependence on Functional p53
John C. Byrd,
Charlotte Shinn,
Jamie K. Waselenko,
Ephraim J. Fuchs,
Teresa A. Lehman,
Phuong L. Nguyen,
Ian W. Flinn,
Louis F. Diehl,
Edward Sausville, and
Michael R. Grever
From the Division of Hematology-Oncology, Walter Reed Army Medical
Center, Washington, DC; the Department of Medicine, Uniformed Services
University of Health Sciences, Bethesda, MD; the Division of
Hematologic Malignancies, Johns Hopkins Oncology Center, Baltimore, MD;
Biotechnologies, Ltd, Laurel, MD; the Department of Laboratory Medicine
and Pathology, University of Minnesota, Minneapolis, MN; and the
Developmental Therapeutics Program, National Cancer Institute,
Bethesda, MD.
Flavopiridol has been reported to induce apoptosis in lymphoid cell
lines via downregulation of bcl-2. The in vitro activity of
flavopiridol against human chronic lymphocytic leukemia (CLL) cells and
potential mechanisms of action for inducing cytotoxicity were studied.
The in vitro viability of mononuclear cells from CLL patients (n = 11) was reduced by 50% at 4 hours, 24 hours, and 4 days at a
flavopiridol concentration of 1.15 µmol/L (95% confidence interval
[CI] ±0.31), 0.18 µmol/L (95% CI
±0.04), and 0.16 µmol/L (95% CI ±0.04), respectively. Loss of
viability in human CLL cells correlated with early induction of
apoptosis. Exposure of CLL cells to 0.18 µmol/L of flavopiridol
resulted in both decreased expression of p53 protein and cleavage of
the caspase-3 zymogen 32-kD protein with the appearance of its 20-kD subunit. Contrasting observations of others in tumor cell lines, flavopiridol cytotoxicity in CLL cells did not correlate with changes
in bcl-2 protein expression alterations. We evaluated flavopiridol's
dependence on intact p53 by exposing splenocytes from wild-type
(p53+/+) and p53 null (p53 /) mice
that demonstrated no preferential cytotoxicity as compared with a
marked differential with F-ara-a and radiation. Incubation of CLL cells
with antiapoptotic cytokine interleukin-4 (IL-4) did not alter the
LC50 of flavopiridol, as compared with a marked elevation
noted with F-ara-a in the majority of patients tested. These data
demonstrate that flavopiridol has significant in vitro activity against
human CLL cells through activation of caspase-3, which appears to occur
independently of bcl-2 modulation, the presence of IL-4, or p53 status.
Such findings strongly support the early introduction of flavopiridol
into clinical trials for patients with B-CLL.
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