The targeting of primary effusion lymphoma cells for apoptosis by inducing lytic replication of human herpesvirus 8 while blocking virus production.
Primary effusion lymphoma (PEL) is a B-cell lymphoma in which human herpesvirus-8 (HHV-8) is found within all tumor cells and represents a target for selectively destroying tumor cells. HHV-8 is latent in most PEL cells and, hence, resistant to antiviral agents that inhibit lytic replication. We demonstrate that PEL cell lines containing HHV-8 without and with coinfection with Epstein-Barr virus responded to the antiseizure medication valproate with entry into the lytic cascade and production of infectious virus. Minimal cell death occurred when noninfected BL-41 cells were incubated with valproate, whereas apoptosis occurred in response to valproate in PELs that supported lytic replication of HHV-8. The anti-viral agents ganciclovir and phosphonoformic acid (PFA) blocked valproate-induced production of infectious virus without blocking entry into the lytic cascade, and apoptosis occurred at levels that were as high as when virus production was not blocked. Ganciclovir and PFA also prevented most valproate-induced expression of the late lytic viral transcript open reading frame 26 (ORF-26), but they did not block the induction of either viral interleukin-6 (vIL-6) or viral G protein-coupled receptor (vGPCR). These studies provide evidence that incubation of PELs with valproate in the presence of ganciclovir or PFA can selectively target tumor cells for apoptosis without increasing viral load.
Klass
Carmen M
CM
Winship Cancer Institute, Emory University, 1365-B Clifton Rd NE, Atlanta, GA 30322, USA.
Krug
Laurie T
LT
Pozharskaya
Veronika P
VP
Offermann
Margaret K
MK
D000998:Antiviral Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D017245:Foscarnet / Q000494:pharmacology; D015774:Ganciclovir / Q000494:pharmacology; D019288:Herpesvirus 8, Human / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D008223:Lymphoma / Q000473:pathology* / Q000821:virology*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology; D014764:Viral Proteins / Q000235:genetics; D019065:Virus Assembly / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D019384:Nucleic Acid Synthesis Inhibitors; D012333:RNA, Messenger; D014764:Viral Proteins; D017245:Foscarnet; D014635:Valproic Acid; D004259:DNA-Directed DNA Polymerase; D015774:Ganciclovir