Differential targeting of protein kinase B in cell death induced by sulindac and its metabolite sulindac sulfide

  • Authors:
    • Anthony Marotta
    • Kuljit Parhar
    • Rajinder Hundal
    • Vincent Duronio
    • Baljinder Salh
  • View Affiliations

  • Published online on: June 1, 2006     https://doi.org/10.3892/ijo.28.6.1471
  • Pages: 1471-1479
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Abstract

Non-steroidal anti-inflammatory drugs such as sulindac inhibit human colorectal carcinogenesis through a mechanism involving the direct inhibition of cyclooxygenase (Cox)-2. However, a wealth of recent evidence indicates that these agents might elicit their effects through mechanisms independently of Cox-2. In this study, we investigated the effects of sulindac and its metabolite, sulindac sulfide on modulation of the critical survival kinase, protein kinase B (PKB). Here, we demonstrate for the first time that treatment with either sulindac or sulindac sulfide results in a decrease in PKB activity, and we provide compelling evidence that this occurs through two distinct mechanisms. Additionally, we report that overexpression of, and conditional activation of PKB attenuates the apoptotic effects of sulindac, but not for sulindac sulfide - the metabolic metabolite of sulindac. We also demonstrate that treatment with sulindac sulfide, but not sulindac, results in a very early robust activation of both caspase-8 and -9. Furthermore, we show that the apoptotic effects of sulindac sulfide can be reverted by both the caspase-8 and -9 inhibitors. Evidence is provided to indicate that PKB is targeted by robust caspase activation due to sulindac sulfide. Hence, further investigation into the mechanisms regulating conversion of sulindac to sulindac sulfide (or direct use of the latter compound), may enhance our ability to target cancers with enhanced signaling through the growth factor↷phosphatidylinositol 3-kinase pathway.

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June 2006
Volume 28 Issue 6

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

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Spandidos Publications style
Marotta A, Parhar K, Hundal R, Duronio V and Salh B: Differential targeting of protein kinase B in cell death induced by sulindac and its metabolite sulindac sulfide. Int J Oncol 28: 1471-1479, 2006
APA
Marotta, A., Parhar, K., Hundal, R., Duronio, V., & Salh, B. (2006). Differential targeting of protein kinase B in cell death induced by sulindac and its metabolite sulindac sulfide. International Journal of Oncology, 28, 1471-1479. https://doi.org/10.3892/ijo.28.6.1471
MLA
Marotta, A., Parhar, K., Hundal, R., Duronio, V., Salh, B."Differential targeting of protein kinase B in cell death induced by sulindac and its metabolite sulindac sulfide". International Journal of Oncology 28.6 (2006): 1471-1479.
Chicago
Marotta, A., Parhar, K., Hundal, R., Duronio, V., Salh, B."Differential targeting of protein kinase B in cell death induced by sulindac and its metabolite sulindac sulfide". International Journal of Oncology 28, no. 6 (2006): 1471-1479. https://doi.org/10.3892/ijo.28.6.1471