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Flavopiridol induces apoptosis in chronic lymphocytic leukemia cells via activation of caspase-3 without evidence of bcl-2 modulation or dependence on functional p53.

Publication ,  Journal Article
Byrd, JC; Shinn, C; Waselenko, JK; Fuchs, EJ; Lehman, TA; Nguyen, PL; Flinn, IW; Diehl, LF; Sausville, E; Grever, MR
Published in: Blood
November 15, 1998

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 micromol/L (95% confidence interval [CI] +/-0.31), 0.18 micromol/L (95% CI +/-0.04), and 0.16 micromol/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 micromol/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.

Duke Scholars

Published In

Blood

ISSN

0006-4971

Publication Date

November 15, 1998

Volume

92

Issue

10

Start / End Page

3804 / 3816

Location

United States

Related Subject Headings

  • bcl-2-Associated X Protein
  • Vidarabine
  • Tumor Suppressor Proteins
  • Tumor Suppressor Protein p53
  • Tumor Cells, Cultured
  • Proto-Oncogene Proteins c-bcl-2
  • Proto-Oncogene Proteins
  • Piperidines
  • Neoplasm Proteins
  • Microtubule-Associated Proteins
 

Citation

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Byrd, J. C., Shinn, C., Waselenko, J. K., Fuchs, E. J., Lehman, T. A., Nguyen, P. L., … Grever, M. R. (1998). Flavopiridol induces apoptosis in chronic lymphocytic leukemia cells via activation of caspase-3 without evidence of bcl-2 modulation or dependence on functional p53. Blood, 92(10), 3804–3816.
Byrd, J. C., C. Shinn, J. K. Waselenko, E. J. Fuchs, T. A. Lehman, P. L. Nguyen, I. W. Flinn, L. F. Diehl, E. Sausville, and M. R. Grever. “Flavopiridol induces apoptosis in chronic lymphocytic leukemia cells via activation of caspase-3 without evidence of bcl-2 modulation or dependence on functional p53.Blood 92, no. 10 (November 15, 1998): 3804–16.
Byrd JC, Shinn C, Waselenko JK, Fuchs EJ, Lehman TA, Nguyen PL, Flinn IW, Diehl LF, Sausville E, Grever MR. Flavopiridol induces apoptosis in chronic lymphocytic leukemia cells via activation of caspase-3 without evidence of bcl-2 modulation or dependence on functional p53. Blood. 1998 Nov 15;92(10):3804–3816.

Published In

Blood

ISSN

0006-4971

Publication Date

November 15, 1998

Volume

92

Issue

10

Start / End Page

3804 / 3816

Location

United States

Related Subject Headings

  • bcl-2-Associated X Protein
  • Vidarabine
  • Tumor Suppressor Proteins
  • Tumor Suppressor Protein p53
  • Tumor Cells, Cultured
  • Proto-Oncogene Proteins c-bcl-2
  • Proto-Oncogene Proteins
  • Piperidines
  • Neoplasm Proteins
  • Microtubule-Associated Proteins