Antiviral interferons induced by Newcastle disease virus (NDV) drive a tumor-selective apoptosis.

Newcastle disease virus (NDV) strongly induces both type I and III antiviral interferons (IFNs-α/-ß and IFN-λ, respectively) in tumor cells while it induces mainly type III IFN in normal cells. Impairment of antiviral type I IFN signaling in tumor cells is thought to be the reason for effective oncolysis. However, there is lack of clarity why lentogenic strain NDV can also induce oncolysis. NDV infection caused apoptosis in normal and tumor cells as demonstrated with the caspase-3 enzyme activation and annexin-V detection. The apoptosis response was inhibited by B18R protein (a type I IFN inhibitor) in tumor cells i.e. A549 and U87MG, and not in normal cells i.e. NB1RGB and HEK293. Similarly, UV-inactivated medium from NDV infection was shown to induce apoptosis in corresponding cells and the response was inhibited in A549 and U87MG cells with the addition of B18R protein. Treatment with combination of IFNs-α/-ß/-λ or IFNs-α/-ß or IFN-λ in NB1RGB, HEK293, A549 and U87MG showed that caspase activity in IFNs-α/-ß/-λ group was the highest, followed with IFN-α/-ß group and IFN-λ group. This suggests that tumor-selectivity of NDV is mainly because of the cumulative effect of type I and III in tumor cells that lead to higher apoptotic effect.

Proinflammatory response induced by Newcastle disease virus in tumor and normal cells.

PURPOSE: To investigate the specific role of immune responses induced by lentogenic Newcastle disease virus (NDV) for its antitumor effect. MATERIALS AND METHODS: NDV LaSota strain was used to infect the following human cells: non-small cell lung carcinoma (A549), glioblastoma (U87MG and T98G), mammary gland adenocarcinoma (MCF7 and MDA-MB-453), hepatocellular carcinoma (Huh7), transformed embryonic kidney cells (HEK293), primary monocytes, lung fibroblast (HF19), skin fibroblast (NB1RGB) and rat astroglia (RCR-1) at 0.001 multiplicity of infection. NDV-induced cytotoxicity and expression of proinflammatory cytokines were analyzed using 3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide assay and multiplex enzyme-linked immunosorbent assay, respectively. RESULTS: Tumor cells (A549, U87MG, T98G, Huh7, MDA-MB-453, and MCF7) showed viability of <44%, while normal cell lines HEK293, NB1RGB, and RCR-1 showed 84%, 73%, and 69% viability at 72 hours postinfection, respectively. Proinflammatory cytokine profiling showed that NDV mainly induced the secretion of interferon (IFN)-α, IFN-ß, and IFN-λ in tumor cells and only IFN-λ in normal cells. In addition, NDV infection induced the production of interleukin (IL)-6 in most cells. CONCLUSION: Our findings suggest a new perspective regarding the role of IFN-λ and IL-6 in the mechanism of tumor selectivity and oncolysis of NDV.