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 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, 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.

Highlights

  • Airway inflammation is a complex process that can be mediated by a variety of stimuli from bacterial infection to allergen exposure

  • Whereas nuclear factor (NF)-κB nuclear translocation in tumor necrosis factor-α (TNF-α)-treated smooth muscle cells is sufficient for the expression of the adhesion molecule vascular adhesion molecule (VCAM)-1, intracellular adhesion molecule (ICAM)-1 expression showed a critical requirement for poly(ADP-ribose) polymerase (PARP)-1

  • The effects of cordycepin on neutrophil recruitment to the lungs of LPS-exposed mice correlate with a general reduction in the expression of inflammatory factors, including the adhesion molecules ICAM-1 and VCAM-1, the cytokines/chemokines monocyte chemotactic protein (MCP)-1, macrophage inflammatory protein (MIP)-1α, MIP-2 and keratinocyte-derived chemokine (KC), and the chemokine receptor CXCR2 (Figure 1B) as assessed by real-time PCR analysis of lung tissues collected 6 h after treatment

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Summary

Introduction

Airway inflammation is a complex process that can be mediated by a variety of stimuli from bacterial infection to allergen exposure. In addition to its effects on cell and tissue homeostasis through the direct utilization of nicotinamide adenine dinucleotide (NAD)+, PARP-1 is increasingly believed to contribute to inflammation by regulating the expression of a variety of inflammatory genes, including adhesion molecules ICAM-1 and VCAM-1, MCP-1, MIP-1α, and a number of other factors (reviewed in 16–18). This function is CORDYCEPIN AND PARP IN INFLAMMATION AND BREAST CANCER linked to the ability of PARP-1 to regulate signal transduction events that result in the activation of the nuclear factor (NF)-κB, extracellular signal-related kinase (ERK), and activator protein 1 (AP1) [19,20,21,22]. Whereas NF-κB nuclear translocation in TNF-α-treated smooth muscle cells is sufficient for the expression of the adhesion molecule VCAM-1, ICAM-1 expression showed a critical requirement for PARP-1

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