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Early Induction of Apoptosis in Hematopoietic Cell Lines After
Exposure to Flavopiridol
Bernard W. Parker,
Gurmeet Kaur,
Wilberto Nieves-Neira,
Mohammed Taimi,
Glenda Kohlhagen,
Tsunehiro Shimizu,
Michael D. Losiewicz,
Yves Pommier,
Edward A. Sausville, and
Adrian M. Senderowicz
From the Laboratories of Biological Chemistry and Molecular
Pharmacology, Division of Basic Sciences, and Laboratory of Drug
Discovery Research and Development and DTP Clinical Trials Unit,
Developmental Therapeutics Program, Division of Cancer Treatment,
Diagnosis and Centers, National Cancer Institute, Bethesda, MD.
Flavopiridol (NSC 649890; Behringwerke L86-8275, Marburg, Germany),
is a potent inhibitor of cyclin dependent kinases (CDKs) 1, 2, and 4. It has potent antiproliferative effects in vitro and is active in tumor
models in vivo. While surveying the effect of flavopiridol on cell
cycle progression in different cell types, we discovered that
hematopoietic cell lines, including SUDHL4, SUDHL6 (B-cell lines),
Jurkat, and MOLT4 (T-cell lines), and HL60 (myeloid), displayed notable
sensitivity to flavopiridol-induced apoptosis. For example, after 100 nmol/L for 12 hours, SUDHL4 cells displayed a similar degree of DNA
fragmentation to that shown by the apoptosis-resistant PC3 prostate
carcinoma cells only after 3,000 nmol/L for 48 hours. After exposure to
1,000 nmol/L flavopiridol for 12 hours, typical apoptotic morphology was observed in SUDHL4 cells, but not in PC3 prostate carcinoma cells
despite comparable potency (SUDHL4:120 nmol/L; PC3: 203 nmol/L) in
causing growth inhibition by 50% (IC50). Flavopiridol did
not induce topoisomerase I or II cleavable complex activity. A relation
of p53, bcl2, or bax protein levels to apoptosis in SUDHL4 was not
appreciated. While flavopiridol caused cell cycle arrest with decline
in CDK1 activity in PC3 cells, apoptosis of SUDHL4 cells occurred
without evidence of cell cycle arrest. These results suggest that
antiproliferative activity of flavopiridol (manifest by cell cycle
arrest) may be separated in different cell types from a capacity to
induce apoptosis. Cells from hematopoietic neoplasms appear in this
limited sample to be very susceptible to flavopiridol-induced apoptosis
and therefore clinical trials in hematopoietic neoplasms should be of
high priority.
Blood, Vol. 91 No. 2 (January 15), 1998:
pp. 458-465
© 1998 by The American Society of Hematology.
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T. V. Achenbach, R. Muller, and E. P. Slater
Bcl-2 Independence of Flavopiridol-induced Apoptosis. MITOCHONDRIAL DEPOLARIZATION IN THE ABSENCE OF CYTOCHROME c RELEASE
J. Biol. Chem.,
October 6, 2000;
275(41):
32089 - 32097.
[Abstract]
[Full Text]
[PDF]
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