A role for MAP kinase in the antitumor activity of a nucleoside analog

Abstract

Nucleoside analogs ( NAs ) have been used extensively in both antitumor and antiviral therapies. Their general mechanism of action has been postulated to result from incorporation into DNA, leading to disruption of DNA synthesis and DNA polymerase inhibition. To further explore the antitumor mechanisms of NAs we have evaluated ganciclovir ( GCV ), an NA antiviral agent, in herpes simplex virus thymidine kinase ( HSV -TK ) gene -modified tumor cells. This system allows specific evaluation of the antitumor effects of NAs because the antitumor effect is directly related to the phosphorylation of the prodrug GCV by the HSV -TK enzyme in the genemodified tumor cells. We demonstrated that GCV incorporates into DNA and inhibits DNA polymerase, as has been observed in HSV -infected cells and with other antitumor NAs in tumor cells. A novel observation is that GCV activates MAP kinase within 1 hour of GCV exposure. This activation directly correlates with cytotoxicity, because inhibition of the MAP kinase extracellular regulated kinase ( Erk ) by PD98059, reversed GCV -mediated cytotoxicity. This effect appears to be specific to the Erk pathway, because inhibition of the p38 kinase with SB203580 had no effect on cytotoxicity. Further, GCV does not act as a DNA -damaging agent or activate general DNA -repair mechanisms, but does produce a number of metabolic disruptions, including a reversible decrease in NAD levels. These effects appear to be downstream of the earlier activation of Erk in this system, which may be a novel mechanism of action for GCV cytotoxicity in HSV -TK gene -modified tumor cells, and thus, needs to be further evaluated as the mechanism of tumor cell killing by other antitumor NAs.

Antiviral Drug Ganciclovir Is a Potent Inhibitor of the Proliferation of Müller Glia–Derived Progenitors During Zebrafish Retinal Regeneration

“…It has been shown that GCV treatment of HSV-TK–expressing tumor cells resulted in the activation of MAP kinase (MAPK). 42 Since MAPK activation is essential for the dedifferentiation of Müller glia and RAG expression after mechanical retinal injury, 13 , 14 it is possible that GCV activated MAPK in Müller glia through an unknown pathway, which in turn led to the high expression of RAGs and subsequent prolonged activation. Another possibility is that there are unknown communicating signals between the dedifferentiated Müller glia and the proliferating MGPCs that function to downregulate RAG expression in Müller glia and promote their transition to a preinjury status.…”