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, Michael R. Grever

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)3804-3816
Number of pages13
JournalBlood
Volume92
Issue number10
StatePublished - Nov 15 1998
Externally publishedYes

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alvocidib
B-Cell Chronic Lymphocytic Leukemia
Caspase 3
Chemical activation
Modulation
Apoptosis
Cytotoxicity
Cells
Confidence Intervals
Interleukin-4
Enzyme Precursors
Proteins

ASJC Scopus subject areas

  • Hematology

Cite this

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.

Flavopiridol induces apoptosis in chronic lymphocytic leukemia cells via activation of caspase-3 without evidence of bcl-2 modulation or dependence on functional p53. / Byrd, John C.; Shinn, Charlotte; Waselenko, Jamie K.; Fuchs, Ephraim J.; Lehman, Teresa A.; Nguyen, Phuong L.; Flinn, Ian W.; Diehl, Louis F.; Sausville, Edward; Grever, Michael R.

In: Blood, Vol. 92, No. 10, 15.11.1998, p. 3804-3816.

Research output: Contribution to journalArticle

Byrd, JC, Shinn, C, Waselenko, JK, Fuchs, EJ, Lehman, TA, Nguyen, PL, Flinn, IW, Diehl, LF, Sausville, E & Grever, MR 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, vol. 92, no. 10, pp. 3804-3816.
Byrd, John C. ; Shinn, Charlotte ; Waselenko, Jamie K. ; Fuchs, Ephraim J. ; Lehman, Teresa A. ; Nguyen, Phuong L. ; Flinn, Ian W. ; Diehl, Louis F. ; Sausville, Edward ; Grever, Michael R. / Flavopiridol induces apoptosis in chronic lymphocytic leukemia cells via activation of caspase-3 without evidence of bcl-2 modulation or dependence on functional p53. In: Blood. 1998 ; Vol. 92, No. 10. pp. 3804-3816.
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title = "Flavopiridol induces apoptosis in chronic lymphocytic leukemia cells via activation of caspase-3 without evidence of bcl-2 modulation or dependence on functional p53",
abstract = "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.",
author = "Byrd, {John C.} and Charlotte Shinn and Waselenko, {Jamie K.} and Fuchs, {Ephraim J.} and Lehman, {Teresa A.} and Nguyen, {Phuong L.} and Flinn, {Ian W.} and Diehl, {Louis F.} and Edward Sausville and Grever, {Michael R.}",
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AU - Waselenko, Jamie K.

AU - Fuchs, Ephraim J.

AU - Lehman, Teresa A.

AU - Nguyen, Phuong L.

AU - Flinn, Ian W.

AU - Diehl, Louis F.

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AU - Grever, Michael R.

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