Journal
MOLECULAR MEDICINE
Volume 17, Issue 9-10, Pages 893-900Publisher
FEINSTEIN INST MED RES
DOI: 10.2119/molmed.2011.00032
Keywords
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Funding
- NIH [HL072889]
- American Cancer Society [RSG-116608]
- Louisiana Cancer Research Consortium (New Orleans, LA)
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Cordycep n 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-1 alpha, MIP-2 and KC, and the chemokine receptor CXCR2. Such a blockade appears to be related to a severe reduction in TNF-alpha expression. Interestingly, in an in vitro system of A549 epithelial cell inflammation, cordycepin effectively blocked LPS-induced, but not INF-alpha-induced, VCAM-1 expression. Such effects correlated with a marked reduction in p65-NE-kappa B 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-kappa B activation and nuclear translocation upon TNF-alpha stimulation resembled the effects achieved upon poly(ADP-ribose) polymerase (PARP) inhibition, suggesting that cordycepin may function as a PARP inhibitor. Indeed, cordycepin blocked H(2)O(2)-induced PARP activation in A549 cells. In a cell-free system, cordycepin inhibited PARP-1 activity at nanomolar concentrations. Similar to PARP inhibitors, cordvcepin 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 corcycepin 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. (C) 2011 The Feinstein Institute for Medical Research, www.feinsteininstitute.org Online address: hffp://www.molmed.org doi: 10.2119/molmed.2011.00032
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