Use of recombinant Newcastle disease virus expressing TRAIL to overcome resistance and enhance apoptosis in colorectal cancer models.

Abstract

e15526 Background: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent, but its efficacy is limited in TRAIL-resistant colorectal cancer (CRC) cells due to low expression of death receptors (DRs). To overcome this resistance, a strategy was sought to enhance TRAIL efficacy in these cells. Methods: To address the resistance, a recombinant Newcastle disease virus (rNDV) encoding the TRAIL gene (rNDV-TRAIL) was developed. The therapeutic potential of rNDV-TRAIL was evaluated in both TRAIL-resistant HT-29 cells and TRAIL-sensitive HCT-116 cells. The effect of rNDV-TRAIL infection on DR expression, apoptosis pathways, and cancer cell death was assessed in vitro. Additionally, in vivo xenograft models were used to test the impact of rNDV-TRAIL treatment on tumor growth and apoptosis. Results: rNDV-TRAIL infection significantly increased DR expression and activated both intrinsic and extrinsic apoptosis pathways. In vitro, rNDV-TRAIL enhanced cancer cell death compared to rNDV alone, particularly in TRAIL-resistant HT-29 cells. In vivo, rNDV-TRAIL treatment suppressed tumor growth and increased apoptosis in HT-29 tumors compared to rNDV or TRAIL protein alone. Mechanistic analyses revealed upregulation of pro-apoptotic proteins (Bax, cleaved caspase-3/-8/-9) and downregulation of anti-apoptotic proteins (Bcl-2), confirming the induction of effective apoptosis. Conclusions: These findings suggest that rNDV-TRAIL represents a promising therapeutic strategy for treating TRAIL-resistant CRC. By sensitizing tumors to TRAIL-induced apoptosis, rNDV-TRAIL enhances overall antitumor efficacy, offering potential for improved treatment outcomes in resistant CRC cases.