Oncolytic Specificity of Newcastle Disease Virus Is Mediated by Selectivity for Apoptosis-Resistant Cells

Abstract

Newcastle disease virus (NDV) is a negative-sense RNA virus that has been shown to possess oncolytic activity. NDV's selective replication in tumor cells has been previously suggested to be due to the lack of a proper antiviral response in these cells. Here we demonstrate that NDV possesses oncolytic activity in tumor cells capable of a robust type I interferon (IFN) response, suggesting that another mechanism underlies NDV's tumor specificity. We show that the oncolytic selectivity of NDV for tumor cells is dependent upon tumor cell resistance to apoptosis. Utilizing the human non-small-cell lung cancer cell line A549 overexpressing the antiapoptotic protein Bcl-xL, we show significant enhancement of oncolytic activity and NDV replication. Interestingly, while the Bcl-xL-overexpressing cells were resistant to apoptotic stimuli induced by chemotherapeutic agents and early viral replication, during the subsequent viral cycles, we observed a paradoxical increase in apoptosis in response to NDV. The increased oncolytic activity seen was secondary to enhanced viral replication and syncytium formation. The induction of a type I IFN response was enhanced in Bcl-xL cells. Overall, these findings propose a new mechanism for cancer cell specificity for NDV, making it an attractive anticancer agent for chemoresistant tumors with enhanced antiapoptotic activity.

Concepts for the Production of Viruses and Viral Vectors in Cell Cultures

“…Viral tropism can be engineered by displaying ligands that bind to cell surface receptors unique to cancer cells [10,[30][31][32]. Several genetically modified viruses have been adapted as potent oncolytic agents for clinical trials, including herpesvirus [33], adenovirus [34], poxvirus [35], coxsackievirus [36], polyovirus [37], Newcastle disease virus [38] and reovirus [39]. In October 2015, the US Food and Drug Administration (FDA) granted approval for the first oncolytic virus (talimogene laherparepvec or T-VEC, brand name IMLYGIC) indicated for cutaneous and nodal melanoma.…”

Loss of stress response as a consequence of viral infection: implications for disease and therapy

“…The observation that virulent strains of NDV impair Hsp70 translation (Collins and Hightower 1982) predicts that these strains could be effective in blocking the establishment of a cytoprotected state and consequently promote apoptosis. Additionally, the oncolytic effect of NDV is enhanced by influenza protein NS1 (Mansour et al 2011). The NS1 protein of the highly pathogenic avian H5N1 influenza virus is currently believed to be responsible for the increased virulence of the strain (Li et al 2006).…”

“…As noted above, like NDV, interferon may function as an oncolytic agent by activating PKR and ultimately impairing Hsp translation in the tumor. In fact, data suggest that NDV induction of interferon may contribute to its oncolytic activity (Mansour et al 2011).…”

Viruses as nanomedicine for cancer

“…19 NDV and VV enter cancer cells by endocytosis, because of the absence of specific receptors for their attachment. 20,21 Poliovirus exhibits greater tropism for neurons, in which it uses CD155 as a receptor (Table 1). 22 Although the receptors such as adenovirus receptors integrin and CAR can be found in normal cells, cancer selectivity is further governed by oncogenes and tumor suppressor genes.…”