Inhibitory effects of cordycepin on cyclic nucleotide-dependent and cyclic nucleotide-independent protein kinases

doi:10.1016/0006-2952(77)90085-5

Biochemical Pharmacology

Volume 26, Issue 14, 15 July 1977, Pages 1287-1290

https://doi.org/10.1016/0006-2952(77)90085-5 Get rights and content

Abstract

The in vitro effect of cordydepin was tested using various protein kinase preparations. These included cyclic AMP-dependent protein kinase (A-PK) from bovine heart, cyclic GMP-dependent protein kinase (G-PK) from fetal guinea pig lung, and two cyclic nucleotide-independent nuclear protein kinases (PK-I and PK-II) prepared from rat hepatoma 3924A and rat liver. The 50 per cent inhibitory concentrations (id₅₀) of cordycepin for A-PK and G-PK ranged from 1.5–5.0 × 10⁻⁴M and 2.5–8.0 × 10⁻⁴ M, respectively, depending on the presence or absence of cyclic AMP and cyclic GMP in the assay. The id₅₀ of cordycepin with either hepatoma 3924A or rat liver PK-I and PK-II was 4.5 × 10⁻⁵ M and 1.0 × 10⁻³ M. respectively. The inhibitory effect of cordycepin was competitive with respect to ATP in all cases. The K_{m} for ATP was increased 3-fold and 5-fold by 5 × 10⁻⁴ M cordycepin for G-PK and A-PK, respectively, while the K_m for ATP was increased 10-fold and 4-fold by 1 × 10⁻³ M cordycepin for PK-I and PK-II, respectively.

References (31)

D.G. Johns et al.
Biochem. Pharmac.
(1976)
H.T. Abelson et al.
Biochim. biophys. Acta
(1972)
M. Delseny et al.
Biochem. biophys. Res. Commun.
(1975)
H. Fouquet et al.
Archs Biochem. Biophys.
(1975)
B. Horowitz et al.
Archs Biochem. Biophys.
(1976)
H. Klenow
Biochim. biophys. Acta
(1963)
M. Adesnik et al.
J. molec. Biol.
(1972)
T. Higashinakagawa et al.
Expl Cell Res.
(1972)
J.F. Kuo et al.
J. biol. Chem.
(1976)
W.N. Kuo et al.
J. biol. Chem.
(1976)

P.G. Plagemann

Archs. Biochem. Biophys.

(1971)

F.R. Butcher et al.

Expl Cell Res.

(1972)

O.J. Martelo et al.

Biochem. biophys. Res. Commun.

(1974)

R.C. Desrosiers et al.

Nucl. Acids. Res.

(1976)

H.E. Kann et al.

Molec. Pharmac.

(1972)

Cited by (14)

Cordycepin (3′-deoxyadenosine) inhibits human platelet aggregation in a cyclic AMP- and cyclic GMP-dependent manner
2007, European Journal of Pharmacology
Cordycepin (3′-deoxyadenosine) is isolated from Cordyceps militaris, a species of the fungal genus Cordyceps. Cordycepin is an ingredient used in traditional Chinese medicine and is prescribed for various diseases, such as cancer and chronic inflammation. In this study, we investigated the novel effect of cordycepin (3′-deoxyadenosine) on collagen-induced human platelet aggregation. Cordycepin inhibited dose-dependently collagen-induced platelet aggregation in the presence of various concentrations of exogenous CaCl₂. Of two aggregation-inducing molecules, cytosolic free Ca²⁺ ([Ca²⁺]_i) and thromboxane A₂ (TXA₂), cordycepin (500 μM) blocked the up-regulation of [Ca²⁺]_i, by up to 74%, but suppressed TXA₂ production by 46%. Subsequently, Ca²⁺-dependent phosphorylation of both 47-kDa and 20-kDa proteins in collagen-treated platelets was potently diminished by cordycepin. However, upstream pathways for producing these two inducers, such as the activation of phospholipase C-γ2 (PLC-γ2) (assessed by the phosphotyrosine level) and the formation of inositol 1,4,5-trisphosphate (IP₃), were not altered by cordycepin. Cordycepin increased the level of second messengers adenosine 3′,5′-cyclic monophosphate (cAMP) and guanosine 3′,5′-cyclic monophosphate (cGMP) in collagen-stimulated platelets. Whereas the NO-sensitive guanylyl cyclase inhibitor ODQ did not alter the cordycepin-induced up-regulation of cGMP, the adenylyl cyclase inhibitor SQ22536 completely blocked the cAMP enhancement mediated by cordycepin, indicating that cordycepin had different modes of action. Therefore, our data suggest that the inhibitory effect of cordycepin on platelet aggregation might be associated with the down-regulation of [Ca²⁺]_i and the elevation of cAMP/cGMP production.
Regulation of bronchoalveolar lavage fluids cell function by the immunomodulatory agents from Cordyceps sinensis
2001, Life Sciences
Cordyceps sinensis (C. sinensis) is one of the well known fungi used in traditional Chinese medicine for treatment asthma and bronchial and lung inflammation. In this study, effects of C. sinensis methanolic extracts on bronchoalveolar lavage fluids (BALF) cells proliferation, inflammatory cytokines production, and genes expression were evaluated. The proliferative response of BALF cells to lipopolysaccharide (LPS) was determined by the tritiated thymidine uptake method. The cell-free supernatants were harvested then tested for interlukin-1β (IL-1β), interlukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-8 (IL-8), interleukin-10 (IL-10), interleukin-12 (IL-12), and interferon-γ (IFN-γ) by the enzyme immunoassay. The results indicated that the CS-19-22 fraction dose dependently suppressed BALF cells proliferation activated by LPS. The CS-19-22 fraction also reduced IL-1β, IL-6, IL-8, IL-10 and TNF-α production in LPS activated BALF cell cultures. Furthermore, the IL-12 and IFN-γ production in activated BALF cells were enhanced by CS-19-22 treatment. The CS-19-22 fraction did not affect IL-1β, IL-6, TNF-α, and IL-8 mRNAs expression in BALF cells detected by reverse transcription-polymerase chain reaction (RT-PCR). By contrast, the CS-19-22 fraction increased IL-12 and IFN-γ mRNAs expression and decreased IL-10 mRNA expression in the BALF cells activated with LPS. These results indicated the CS-19-22 fraction suppressed IL-1β, IL-6, TNF-α, and IL-8 cytokines production in BALF cells through other than inhibition of mRNAs expression pathway. These results also demonstrate that the therapeutic activity of C. sinensis in Chinese medicine may be related to modulation of T_H1 and T_H2 cells functions in bronchial airway.
Selective stimulation by mitogens of incorporation of <sup>35</sup>S-methionine into a family of proteins released into the medium by 3T3 cells
1980, Cell
Serum and three mitogens for mouse embryo 3T3 cells—fibroblast growth factor from brain, fibroblast growth factor from pituitary, and epidermal growth factor—specifically stimulate the synthesis and release into the medium by these cells of a group of proteins that travel together on SDS gel electrophoresis and that are detected by ³⁵S-methionine labeling. These proteins, designated mitogen-releasable proteins (MRPs), have a median, monomer molecular weight on SDS polyacrylamide gel electrophoresis of 34,000 daltons (30,000–38,000 daltons). Our evidence indicates that these proteins comprise a family of glycoproteins, probably with a common polypeptide backbone. The observations supporting this conclusion are that MRPs give a diffuse pattern of bands upon SDS gel electrophoresis; travel as a single, diffuse band when resolved by electrophoresis in the absence of SDS; adsorb to a pea-lectin-sepharose column and can be eluted with α-methyl mannose; and can be labeled metabolically with ³H-mannose. In addition, in the presence of tunicamycin, MRPs are not made—instead, a smaller molecular weight (22,000 dalton), and apparently homogeneous, protein appears. We believe this 22,000 dalton protein to be the unglycosylated form of MRP. Further support for this idea comes from our observation that treatment of MRPs with endoglycosidase H produces a protein with a molecular weight slightly greater than 22,000 daltons. The effect of mitogens on DNA synthesis and MRP release are correlated in the following ways. First, serum factors are required for both responses. Second, in 3T3 cells transformed by SV40, Moloney and Kirsten viruses that do not synthesize DNA in response to FGF, MRPs are not released in response to FGF. Third, in untransformed 3T3 cells, the dose-response curves for fibroblast growth factor on MRP release and thymidine incorporation are closely correlated. Fourth, insulin, a poor mitogen for 3T3 cells, does not enhance MRP release. Fifth, stimulation of MRP release by epidermal growth factor or fibroblast growth factor is inhibited by hydroxyurea and butyrate, both inhibitors of DNA synthesis in these cells. Sixth, if the mitogen is removed at any time during the 20 hr preincubation period, the effect on MRP release observed between 20 and 24 hr is severely diminished.
Modulation of Cyclic Nucleotide Metabolism and Function by Xenobiotics
1980, Annual Reports in Medicinal Chemistry
This chapter reviews the identification and development of exogenous effectors of cyclic nucleotide metabolism and function since 1977. The chapter describes and investigates Guanylate cyclase and cGMP dependent protein kinase that are functionally similar to their counterparts. Yet, there lies much less understanding of the role of cGMP in either physiology or pathophysiology. D-lysergic acid diethylamide (LSD) and some derivatives can increase activity of a serotonin-responsive adenylate cyclase from the liver fluke. Xanthines continue to generate interest as inhibitors of phosphodiesterase (PDE) and as potential therapeutic agents. HWA inhibited CAMP PDE from bovine bronchi in more potent fashion than aminophylline. PDE inhibitors can also affect cardiovascular function. Antipsychotic drugs from a number of chemical classes displayed high-affinity, calcium-dependent binding to the calcium-dependent activator of cyclic nucleotide PDE. The relationship of this property to clinical efficacy is still unclear. Paraquat, a guanylate cyclase stimulator, can, at higher concentrations, block the cyclic nucleotide increases in rat lung slices caused by histamine or isoproterenol. Sodium nitroprusside that decreases cyclic AMP levels in bovine parathyroid cells stimulated by isoproterenol, dopamine, and choleratoxin elevates the cGMP levels in these cells by itself.
Naturally Occurring Nucleoside and Nucleotide Antibiotics
1979, Progress in Nucleic Acid Research and Molecular Biology
This chapter reviews that three of the naturally occurring nucleoside antibiotics—that is, tubercidin, 5-azacytidine, and ara-A—have been successfully used in humans as antineoplastic and antiviral agents. A fourth antibiotic, pyrazofurin, is undergoing clinical testing as an antineoplastic agent for carcinoma of the breast. In addition to the health-related application of these naturally occurring nucleoside and nucleotide antibiotics, some have found application as antifungal agents. The chapter discusses that once the structures of some of the nucleoside antibiotics establish, it is possible in some cases to predict the cellular reaction which would be affected by them. The pyrimidine nucleoside antibiotics, which resemble the -CCA terminus of tRNA, bind to ribosomal peptidyltransferase and inhibit protein synthesis in prokaryotes and eukaryotes. Two adenosine analogs, agrocin 84 and thuringiensin, have been isolated as nucleotides. Agrocin 84 prevents cell growth, most probably by interacting with receptor sites on bacterial cell surfaces. Thuringiensin, as a nucleotide, is taken up by mammalian cells and acts as an ATP analog. The aim of this chapter is to evaluate the progress that has been made in the nucleoside antibiotics. Two nucleosides, eritadenine and clitidine, although not antibiotics, are also discussed because of their biological properties.
Cordycepin (3-deoxyadenosine) has an anti-platelet effect by Regulating the cGMP-Associated pathway of human platelet activation
2007, Journal of Food Science and Nutrition

View all citing articles on Scopus

^☆: This research was supported by Grant CA-14162 (RIG) from the National Cancer Institute and Grant HL-15696 (JFK) from the National Heart and Lung Institute.

View full text

Inhibitory effects of cordycepin on cyclic nucleotide-dependent and cyclic nucleotide-independent protein kinases☆

Abstract

Biochem. Pharmac.

Biochim. biophys. Acta

Biochem. biophys. Res. Commun.

Archs Biochem. Biophys.

Archs Biochem. Biophys.

Biochim. biophys. Acta

J. molec. Biol.

Expl Cell Res.

J. biol. Chem.

J. biol. Chem.

Archs. Biochem. Biophys.

Expl Cell Res.

Biochem. biophys. Res. Commun.

Nucl. Acids. Res.

Molec. Pharmac.