Induction of apoptosis by a Newcastle disease virus vaccine (MTH-68/H) in PC12 rat phaeochromocytoma cells

The attenuated Newcastle Disease Virus (NDV) vaccine MTH-68/H has been Soun d to cause regression of various tumors including cel min types of human ne oplasms (See Table I ann References 86-88). The mechanism of its oncolytic action is poorly understood, but it appears to affect specific signaling pa thways in the tal;Set cell. We studied the cellular effects of NDV employin g PC12 rat phaeochromocytoma cells, a widely used model system to analyze d ifferentiation, proliferation and apoptosis. The MTH-68/H vaccine was found to be cytotoxic on PC12 cells. It caused internucleosomal DNA fragmentatio n, the most characteristic feature of programmed cell death (PCD). A brief exposure (30 min) of P12 cells to the virus was sufficient to produce a ful l-blown apoptotic response. Major mitogen-activated protein kinase pathways (including the stress inducible c-Jun N-terminal kinase pathway and p38 pa thway) or mechanisms regulated by reactive oxygen species appear to have no role in virus-induced cell death. The PCD-inducing effect of MTH-68/H coul d nor be prevented by simultaneous treatment of the P12 cells with growth f actors or second messenger analogs stimulating protein kinase C or Ca++-med iated pathways. In contrast, treatment with a cyclic AMP analog partially p rotected the them from virus-induced apoptosis. These experimental results suggests that MTH-68/H might disrupt a growth factor-stimulated survival pa thway and that direct stimulation of protein kinase A-catalyzed phosphoryla tion events bypass this NDV-induced block.