7-Hydroxystaurosporine (UCN-01) and ionizing radiation combine to inhibit the growth of Bcl-2-overexpressing U937 leukemia cells through a non-apoptotic mechanism

  • Authors:
    • Leanne Cartee
    • Heidi Sankala
    • Christine Davis
    • Rebecca Smith
    • Sonia Maggio
    • Peck-Sun Lin
    • Paul Dent
    • Steven Grant
  • View Affiliations

  • Published online on: August 1, 2002     https://doi.org/10.3892/ijo.21.2.351
  • Pages: 351-359
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Abstract

A clinically relevant dose (2.0 Gy) of ionizing radiation (IR) was employed to determine if subsequent exposure to the protein kinase C (PKC) and Chk 1 inhibitor UCN-01 for 24 h could abrogate IR-induced G2/M arrest and promote apoptosis in U937 leukemic cells ectopically expressing Bcl-2 (U937/Bcl-2). To this end, empty-vector control (U937/pCEP4) and U937/Bcl-2 cells were exposed to two UCN-01 concentrations following IR: i) a 50 nM concentration, which by itself was minimally toxic to both cell lines, and ii) a 150 nM concentration, which modestly induced apoptosis (e.g., ~19%) in control cells after 24 h. The effects of UCN-01 on IR responses were examined in relation to apoptosis induction, suspension culture growth inhibition, loss of clonogenic survival, and cell cycle perturbations. IR (2 Gy) alone minimally induced apoptosis in both U937 transfectant cell lines (e.g., <5% at 24 h in each case). Although UCN-01 failed to potentiate IR-mediated apoptosis at either early (e.g., 24 h) or late (e.g., 72 h) intervals, exposure to 50 or 150 nM UCN-01 resulted in a significant, albeit modest, reduction in proliferation and colony formation in irradiated U937/pCEP4 and U937/Bcl-2 cells. Despite failing to enhance apoptosis, UCN-01 treatment abrogated IR-induced G2/M arrest in both cell lines, an event associated with enhanced activation of cyclin-dependent kinase 1 (cdk1), promotion of G0/G1 arrest, and dephosphorylation of the retinoblastoma protein (pRb). Together, these findings indicate that exposure of U937 cells ectopically-expressing Bcl-2 to the combination of UCN-01 + IR leads to a further reduction in cell proliferation, and that this phenomenon appears to involve a non-apoptotic mechanism.

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August 2002
Volume 21 Issue 2

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

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Spandidos Publications style
Cartee L, Sankala H, Davis C, Smith R, Maggio S, Lin P, Dent P and Grant S: 7-Hydroxystaurosporine (UCN-01) and ionizing radiation combine to inhibit the growth of Bcl-2-overexpressing U937 leukemia cells through a non-apoptotic mechanism. Int J Oncol 21: 351-359, 2002.
APA
Cartee, L., Sankala, H., Davis, C., Smith, R., Maggio, S., Lin, P. ... Grant, S. (2002). 7-Hydroxystaurosporine (UCN-01) and ionizing radiation combine to inhibit the growth of Bcl-2-overexpressing U937 leukemia cells through a non-apoptotic mechanism. International Journal of Oncology, 21, 351-359. https://doi.org/10.3892/ijo.21.2.351
MLA
Cartee, L., Sankala, H., Davis, C., Smith, R., Maggio, S., Lin, P., Dent, P., Grant, S."7-Hydroxystaurosporine (UCN-01) and ionizing radiation combine to inhibit the growth of Bcl-2-overexpressing U937 leukemia cells through a non-apoptotic mechanism". International Journal of Oncology 21.2 (2002): 351-359.
Chicago
Cartee, L., Sankala, H., Davis, C., Smith, R., Maggio, S., Lin, P., Dent, P., Grant, S."7-Hydroxystaurosporine (UCN-01) and ionizing radiation combine to inhibit the growth of Bcl-2-overexpressing U937 leukemia cells through a non-apoptotic mechanism". International Journal of Oncology 21, no. 2 (2002): 351-359. https://doi.org/10.3892/ijo.21.2.351