Vincristine induced apoptosis in acute lymphoblastic leukaemia cells: A mitochondrial controlled pathway regulated by reactive oxygen species?

  • Authors:
    • E. Groninger
    • G. J. Meeuwsen-De Boer
    • S. S.N. De Graaf
    • W. A. Kamps
    • E. S.J.M. De Bont
  • View Affiliations

  • Published online on: December 1, 2002     https://doi.org/10.3892/ijo.21.6.1339
  • Pages: 1339-1345
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Abstract

Vincristine (VCR), a microtubule interfering anti-cancer agent, plays a key role in the treatment of childhood acute lymphoblastic leukaemia (ALL). The route of VCR induced apoptosis in ALL cells is not well defined. In this study we demonstrated caspase-9 and -3 activation in vivo in bone marrow leukaemic cells of a child with newly diagnosed ALL, after treatment with a single dose of VCR. We hypothesized that VCR induced apoptosis in ALL cells proceeds by a mitochondrial controlled pathway. We further studied the route of VCR induced apoptosis in Jurkat acute lymphoblastic leukaemia cells. First we showed that VCR induces activation of caspase-9 and -3 in Jurkat cells. With the caspase-9 inhibitor Z-LEHD-FMK we proved that caspase-9 was activated prior to caspase-3. Loss of mitochondrial transmembrane potential was independent of caspase-9 activation. To confirm the mitochondrial role in VCR induced apoptosis, the effect of blocking the mitochondrial route upstream of caspase-9 activation was investigated at two different levels: reactive oxygen species (ROS) scavenging and Bcl-2 overexpression. Generation of ROS was detected early in Jurkat cells during VCR exposure. Ascorbic acid, a ROS scavenger, inhibited ROS generation as well as caspase-9 and -3 activation and cell death induced by VCR. Furthermore, in Bcl-2 overexpressing Jurkat cells mitochondrial membrane potential changes, caspase-9 and -3 activation and cell death upon VCR exposure were decreased, in comparison to parental Jurkat cells. However, generation of ROS was not decreased in Jurkat cells with Bcl-2 overexpression. We concluded that ROS play a regulatory role in the initial phase of a mitochondrial controlled pathway of VCR induced apoptosis in Jurkat cells.

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December 2002
Volume 21 Issue 6

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Groninger E, Meeuwsen-De Boer GJ, De Graaf SS, Kamps WA and De Bont ES: Vincristine induced apoptosis in acute lymphoblastic leukaemia cells: A mitochondrial controlled pathway regulated by reactive oxygen species?. Int J Oncol 21: 1339-1345, 2002
APA
Groninger, E., Meeuwsen-De Boer, G.J., De Graaf, S.S., Kamps, W.A., & De Bont, E.S. (2002). Vincristine induced apoptosis in acute lymphoblastic leukaemia cells: A mitochondrial controlled pathway regulated by reactive oxygen species?. International Journal of Oncology, 21, 1339-1345. https://doi.org/10.3892/ijo.21.6.1339
MLA
Groninger, E., Meeuwsen-De Boer, G. J., De Graaf, S. S., Kamps, W. A., De Bont, E. S."Vincristine induced apoptosis in acute lymphoblastic leukaemia cells: A mitochondrial controlled pathway regulated by reactive oxygen species?". International Journal of Oncology 21.6 (2002): 1339-1345.
Chicago
Groninger, E., Meeuwsen-De Boer, G. J., De Graaf, S. S., Kamps, W. A., De Bont, E. S."Vincristine induced apoptosis in acute lymphoblastic leukaemia cells: A mitochondrial controlled pathway regulated by reactive oxygen species?". International Journal of Oncology 21, no. 6 (2002): 1339-1345. https://doi.org/10.3892/ijo.21.6.1339