Reversible restriction of vesicular stomatitis virus in permissive cells treated with inhibitors of prostaglandin biosynthesis.
Indomethacin, a potent nonsteroidal inhibitor of prostaglandin synthetase (cyclooxygenase) reduced yields of infectious vesicular stomatitis virus in HEp-2 cells more than 99% if added to cultures at levels of 10(-3)M either before or after infection. Other permissive cell lines differed according to the treatment period and drug level required for restricting productive infections. The inhibitory effect of indomethacin was progressively reduced if infection of cells was delayed for increasing times after drug removal. Strong inhibition of viral replication also occurred in cells treated with the cyclooxygenase antagonists naproxen, phenylbutazone, and oxyphenylbutazone whereas phenacetin, which does not block cyclooxygenase function, was inactive. Enhanced viral replication occurred in indomethacin-treated HEp-2 cultures when these cells were subsequently exposed to such substances as prostaglandin E1, cyclic AMP, or insulin. Conversely, indomethacin-treated cells remained restrictive for VSV if they were subsequently exposed to metabolic inhibitors of functional DNA (actinomycin D or mitomycin C), messenger RNA synthesis (alpha-amanitin), or protein synthesis (cycloheximide) at concentrations that normally do not compromise viral replication. Pretreatment of HEp-2 cells with mitomycin C markedly shifted the dose response for indomethacin-mediated inhibition of VSV from a 90% inhibitory dose of about 10(-4)M to one of 10(-9)M or lower. These findings suggest that preexisting host factors essential for replication of VSV, although rendered nonfunctional by the drug indomethacin, can be replenished unless their synthesis is blocked by various classes of metabolic inhibitors.
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000633:toxicity*; D002294:Carcinoma, Squamous Cell; D002460:Cell Line; D006224:Cricetinae; D016861:Cyclooxygenase Inhibitors; D006367:HeLa Cells / Q000502:physiology; D006801:Humans; D007213:Indomethacin / Q000633:toxicity*; D007668:Kidney; D016685:Mitomycin; D008937:Mitomycins / Q000633:toxicity; D014721:Vesicular stomatitis Indiana virus / Q000187:drug effects / Q000254:growth & development*
D000893:Anti-Inflammatory Agents; D016861:Cyclooxygenase Inhibitors; D008937:Mitomycins; D016685:Mitomycin; D007213:Indomethacin