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Molecular Medicine

, Volume 17, Issue 9–10, pp 893–900 | Cite as

Cordycepin Blocks Lung Injury-Associated Inflammation and Promotes BRCA1-Deficient Breast Cancer Cell Killing by Effectively Inhibiting PARP

  • Hogyoung Kim
  • Amarjit S. Naura
  • Youssef Errami
  • Jihang Ju
  • A. Hamid Boulares
Research Article

Abstract

Cordycepin has been shown to interfere with a myriad of molecular processes from RNA elongation to kinase activity, and prevents numerous inflammatory processes in animal models. Here we show in a mouse model of LPS-induced acute lung injury that cordycepin prevents airway neutrophilia via a robust blockade of expression of several inflammatory genes, including the adhesion molecule ICAM-1 and VCAM-1, the cytokine/chemokine MCP-1, MIP-1α, MIP-2 and KC, and the chemokine receptor CXCR2. Such a blockade appears to be related to a severe reduction in TNF-α expression. Interestingly, in an in vitro system of A549 epithelial cell inflammation, cordycepin effectively blocked LPS-induced, but not TNF-α-induced, VCAM-1 expression. Such effects correlated with a marked reduction in p65-NF-κB activation as assessed by its phosphorylation at serine-536 but without an apparent effect on its nuclear translocation. The effects of cordycepin on the expression of VCAM-1 and ICAM-1, and of NF-κB activation and nuclear translocation upon TNF-α stimulation resembled the effects achieved upon poly(ADP-ribose) polymerase (PARP) inhibition, suggesting that cordycepin may function as a PARP inhibitor. Indeed, cordycepin blocked H2O2-induced PARP activation in A549 cells. In a cell-free system, cordycepin inhibited PARP-1 activity at nanomolar concentrations. Similar to PARP inhibitors, cordycepin significantly induced killing of breast cancer susceptibility gene (BRCA1)-deficient MCF-7 cells, supporting its therapeutic use for the treatment of BRCA-deficient breast cancers. With added antiinflammatory characteristics, therapies that include cordycepin may prevent potential inflammation triggered by traditional chemotherapeutic drugs. Cordycepin, to the best of our knowledge, represents the first natural product possessing PARP inhibitory traits.

Notes

Acknowledgments

This work was supported, in part, by grant HL072889 from the NIH and grant RSG-116608 from the American Cancer Society as well as funds from the Louisiana Cancer Research Consortium (New Orleans, LA) to H Boulares.

Supplementary material

10020_2011_1709893_MOESM1_ESM.pdf (1 mb)
Cordycepin Blocks Lung Injury-Associated Inflammation and Promotes BRCA1-Deficient Breast Cancer Cell Killing by Effectively Inhibiting PARP

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Copyright information

© The Feinstein Institute for Medical Research 2011
www.feinsteininstitute.org

Authors and Affiliations

  • Hogyoung Kim
    • 1
  • Amarjit S. Naura
    • 1
  • Youssef Errami
    • 1
  • Jihang Ju
    • 1
  • A. Hamid Boulares
    • 1
  1. 1.The Stanley Scott Cancer Center, and the Department of Pharmacology and Experimental TherapeuticsLouisiana State University Health Sciences CenterNew OrleansUSA

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