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Mechanisms of enhancement of TRAIL tumoricidal activity against human cancer cells of different origin by dipyridamole

Oncogene volume 27, pages 3435–3445 (2008)Cite this article

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has emerged as an attractive cytokine that selectively targets cancer cells, however its efficacy has been challenged by a number of resistance mechanisms. Therefore, the current study investigated the potential of dipyridamole to enhance TRAIL efficacy and the probable underlying mechanisms. Dipyridamole dramatically sensitized p53-mutant human cancer cell lines: SW480, MG63 and DU145, to the antitumor activity of TRAIL, as evidenced by enabling TRAIL to efficiently cleave initiator and executioner caspases. Although dipyridamole upregulated both DR4 and DR5 and increased their cell surface expression, RNA interference revealed a preferential dependence on DR5. Moreover, dipyridamole inhibited survivin expression and its important consequences were confirmed by small interfering RNA. Mechanistically, dipyridamole induced transcriptional shutdown of survivin expression accompanying G1 arrest that was characterized by downregulation of D-type cyclins and cdk6. In addition, a transcriptional mechanism powered by CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) induction was responsible for DR5 upregulation by dipyridamole. Importantly, dipyridamole-induced enhancement of TRAIL efficacy and alterations of protein expression were independent of either protein kinase A or protein kinase G. In conclusion, findings of the present study described novel mechanisms of dipyridamole action and highlighted its promising use as a potential enhancer of TRAIL efficacy.

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Acknowledgements

This work was supported in part by The Japanese Ministry of Education, Culture, Sports, Science and Technology.

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Authors and Affiliations

  1. Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan

    A E Goda, T Yoshida, M Horinaka, T Yasuda, M Wakada & T Sakai

  2. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt

    A E Goda

  3. Department of Urology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan

    T Yasuda & T Shiraishi

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  1. A E Goda
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  2. T Yoshida
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  3. M Horinaka
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  4. T Yasuda
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  5. T Shiraishi
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  6. M Wakada
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  7. T Sakai
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Correspondence to T Sakai.

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Goda, A., Yoshida, T., Horinaka, M. et al. Mechanisms of enhancement of TRAIL tumoricidal activity against human cancer cells of different origin by dipyridamole. Oncogene 27, 3435–3445 (2008). https://doi.org/10.1038/sj.onc.1211008

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