Aspirin inhibits camptothecin-induced p21CIP1 levels and potentiates apoptosis in human breast cancer cells

  • Authors:
    • Lloyd F. Alfonso
    • Kalkunte S. Srivenugopal
    • Thiruma V. Arumugam
    • Thomas J. Abbruscato
    • Jon A. Weidanz
    • G. Jayarama Bhat
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  • Published online on: March 1, 2009     https://doi.org/10.3892/ijo_00000185
  • Pages: 597-608
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Abstract

The ability of aspirin to trigger apoptosis in cancer cells is well known and is consistent with the clinical and epidemiological evidence on its chemopreventive effects in curtailing epithelial cancers, including breast cancer. We hypothesized that the anticancer effects of aspirin may involve acetylation of the tumor suppressor protein p53, a known regulator of apoptosis. In the present study, we determined if aspirin at the physiologically achievable concentration of 100 µM acetylates p53 and modulates the expression of p21CIP1, a protein involved in cell cycle arrest, and Bax, a pro-apoptotic protein. Using MDA-MB-231 human breast cancer cells, we demonstrate that aspirin at 100 µM concentration markedly acetylated the p53 protein, which was primarily localized to the nucleus. Aspirin induced p21CIP1 protein levels in a transient fashion in contrast to the sustained induction of Bax. The induction of p21CIP1 protein levels began at 3 h and was maximal at 6-8 h; however, it decreased to control levels by 30 h. In contrast, the anticancer drug, camptothecin (CPT) induced a steady accumulation of p21CIP1 protein. Remarkably, when cells were co-treated with aspirin and CPT, p21CIP1 levels were drastically downregulated, and this phenomenon was observed in many cancer cell lines. Incubation of recombinant p21 with cytoplasmic extracts from aspirin-treated cells caused its degradation suggesting the involvement of proteases in the disappearance of p21CIP1. Consistent with this data, aspirin decreased the survival of CPT-treated cells and greatly increased the extent of apoptosis. Our observation that aspirin has the ability to inhibit p21CIP1 after its initial induction has important implications in chemotherapy, and suggests its potential use to increase the efficacy of anticancer agents.

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March 2009
Volume 34 Issue 3

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

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APA
Alfonso, L.F., Srivenugopal, K.S., Arumugam, T.V., Abbruscato, T.J., Weidanz, J.A., & Bhat, G.J. (2009). Aspirin inhibits camptothecin-induced p21CIP1 levels and potentiates apoptosis in human breast cancer cells. International Journal of Oncology, 34, 597-608. https://doi.org/10.3892/ijo_00000185
MLA
Alfonso, L. F., Srivenugopal, K. S., Arumugam, T. V., Abbruscato, T. J., Weidanz, J. A., Bhat, G. J."Aspirin inhibits camptothecin-induced p21CIP1 levels and potentiates apoptosis in human breast cancer cells". International Journal of Oncology 34.3 (2009): 597-608.
Chicago
Alfonso, L. F., Srivenugopal, K. S., Arumugam, T. V., Abbruscato, T. J., Weidanz, J. A., Bhat, G. J."Aspirin inhibits camptothecin-induced p21CIP1 levels and potentiates apoptosis in human breast cancer cells". International Journal of Oncology 34, no. 3 (2009): 597-608. https://doi.org/10.3892/ijo_00000185