Single-drug effects of KSHV reactivation and related cellular signaling.

Abstract

<p>(A) Shown are the five drugs that are used in the drug combinations and the mechanisms by which they induce KSHV reactivation. The diagram also illustrates the known crosstalk among these five drugs. : Synergistic effect; : Inhibitory effect. Representative known interactions among different molecules: a. Proteasome inhibitor prevents the activation of NF-kB <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0020998#pone.0020998-Adams1" target="_blank">[43]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0020998#pone.0020998-Adams2" target="_blank">[44]</a>. b. PKC activates NF-kB in T and B lymphocytes <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0020998#pone.0020998-Krappmann1" target="_blank">[45]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0020998#pone.0020998-Williams1" target="_blank">[46]</a>. c. NF-kB inhibits herpesvirus reactivation <i>in vitro</i> and <i>in vivo </i><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0020998#pone.0020998-Brown1" target="_blank">[13]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0020998#pone.0020998-Krug1" target="_blank">[47]</a>. d. Glucocorticoids such as Dexamethasone inhibit NF-kB activity through induction of IkB <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0020998#pone.0020998-Auphan1" target="_blank">[48]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0020998#pone.0020998-Ayroldi1" target="_blank">[49]</a>. e. Dexamethasone and cAMP may synergistically regulate the expression of a subset of genes in lymphocytes <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0020998#pone.0020998-Dowd1" target="_blank">[40]</a>. f. PKA pathway and PKC pathway can synergize <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0020998#pone.0020998-Rabbi1" target="_blank">[50]</a> or antagonize <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0020998#pone.0020998-HermannKleiter1" target="_blank">[51]</a> each other in different circumstances. (B) Shown are the KSHV reactivation rates upon treatment with the five drugs individually (Blue: Bortezomib, Red: db-cAMP, Green: Prostratin, Purple: Valproate, Cyan: Dexamethasone). The nine concentrations used are nine two-fold dilutions of the following maximum concentrations for the drugs Bortezomib 320(nM), db-cAMP 8(mM), Prostratin 80(uM), Valproate 6(mM), Dexamethasone 400(nM). The concentrations are also the nine concentrations (Conc. I) in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0020998#pone-0020998-t001" target="_blank">Table 1</a>.</p