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The cyclin-dependent kinase inhibitor SNS-032 induces apoptosis in breast cancer cells via depletion of Mcl-1 and X-linked inhibitor of apoptosis protein and displays antitumor activity in vivo

  • Authors:
    • Gui'e Xie
    • Hongping Tang
    • Shaoqing Wu
    • Jingsong Chen
    • Jiangwen Liu
    • Can Liao

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  • Published online on: May 26, 2014     https://doi.org/10.3892/ijo.2014.2467
  • Pages: 804-812
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Abstract

Inhibitors of cyclin-dependent kinases (Cdks) have been reported to have activities in many types of cancer cells by inhibiting Cdk7 and Cdk9, which control transcription. SNS-032 is a potent and selective inhibitor of Cdk2, Cdk7 and Cdk9 and has emerged in clinical trials. Here, we examined the viability of MCF-7 and MDA-MB-435 breast cancer cells in the presence of SNS-032 and observed a dose-dependent inhibition of cellular proliferation in both cell lines. SNS-032 had a direct apoptosis-inducing effect through both the extrinsic and intrinsic apoptotic pathways in breast cancer cells as shown by a dose-dependent increase in Annexin V-positive cells and terminal deoxynucleotidyl transferase-mediated dUTP nick?end labeling (TUNEL)-positive cells, as well as activation of caspase-8, -9 and poly(ADP-ribose) polymerase (PARP). At the molecular level, SNS-032 induced a marked dephosphorylation of serine 2 and 5 of RNA polymerase (RNA Pol) II and blocked RNA synthesis. Consistent with the inherently rapid turnover rates of their transcripts and proteins, the anti-apoptotic proteins Mcl-1 and X-linked inhibitor of apoptosis protein (XIAP) were rapidly reduced on exposure to SNS-032. Our results also indicated that SNS-032 suppressed the growth of breast cancer xenografts in mice. These data demonstrate that the use of SNS-032 may be a rational and novel therapeutic strategy for human breast cancer and warrants further clinical investigation.
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August-2014
Volume 45 Issue 2

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

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  • Journal Metrics
  • Impact Factor: 4.5
  • Ranked Oncology
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  • CiteScore: 9.6
  • CiteScore Rank: Q1: #66/404 Oncology
  • Source Normalized Impact per Paper (SNIP): 0.88
  • SCImago Journal Rank (SJR): 1.099
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Spandidos Publications style
Xie G, Tang H, Wu S, Chen J, Liu J and Liao C: The cyclin-dependent kinase inhibitor SNS-032 induces apoptosis in breast cancer cells via depletion of Mcl-1 and X-linked inhibitor of apoptosis protein and displays antitumor activity in vivo. Int J Oncol 45: 804-812, 2014.
APA
Xie, G., Tang, H., Wu, S., Chen, J., Liu, J., & Liao, C. (2014). The cyclin-dependent kinase inhibitor SNS-032 induces apoptosis in breast cancer cells via depletion of Mcl-1 and X-linked inhibitor of apoptosis protein and displays antitumor activity in vivo. International Journal of Oncology, 45, 804-812. https://doi.org/10.3892/ijo.2014.2467
MLA
Xie, G., Tang, H., Wu, S., Chen, J., Liu, J., Liao, C."The cyclin-dependent kinase inhibitor SNS-032 induces apoptosis in breast cancer cells via depletion of Mcl-1 and X-linked inhibitor of apoptosis protein and displays antitumor activity in vivo". International Journal of Oncology 45.2 (2014): 804-812.
Chicago
Xie, G., Tang, H., Wu, S., Chen, J., Liu, J., Liao, C."The cyclin-dependent kinase inhibitor SNS-032 induces apoptosis in breast cancer cells via depletion of Mcl-1 and X-linked inhibitor of apoptosis protein and displays antitumor activity in vivo". International Journal of Oncology 45, no. 2 (2014): 804-812. https://doi.org/10.3892/ijo.2014.2467