Targeting β-catenin using XAV939 nanoparticle promotes immunogenic cell death and suppresses conjunctival melanoma progression

• Published in: International journal of pharmaceutics Vol. 640; p. 123043
• Main Authors: Antony, Ferrin, Kang, Xuejia, Pundkar, Chetan, Wang, Chuanyu, Mishra, Amarjit, Chen, Pengyu, Babu, R. Jayachandra, Suryawanshi, Amol
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 10.06.2023
• Subjects: Animals; beta Catenin - genetics; beta Catenin - metabolism; beta Catenin - pharmacology; Cell Line, Tumor; Conjunctival melanoma; Immunogenic Cell Death; Immunogenic cell death (ICD); Melanoma - drug therapy; Tumor microenvironment (TME); Wnt Signaling Pathway; XAV939; β-catenin; Tumor microenvironment (TME); β-catenin; XAV939; Immunogenic cell death (ICD); Conjunctival melanoma
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2023.123043

[Display omitted] Many tumors dysregulate Wnt/β-catenin pathway to promote stem-cell-like phenotype, tumorigenesis, immunosuppression, and resistance to targeted cancer immunotherapies. Therefore, targeting this pathway is a promising therapeutic approach to suppress tumor progression and elicit robust anti-tumor immunity. In this study, using a nanoparticle formulation for XAV939 (XAV-Np), a tankyrase inhibitor that promotes β-catenin degradation, we investigated the effect of β-catenin inhibition on melanoma cell viability, migration, and tumor progression using a mouse model of conjunctival melanoma. XAV-Nps were uniform and displayed near-spherical morphology with size stability for upto 5 days. We show that XAV-Np treatment of mouse melanoma cells significantly suppresses cell viability, tumor cell migration, and tumor spheroid formation compared to control nanoparticle (Con-Np) or free XAV939-treated groups. Further, we demonstrate that XAV-Np promotes immunogenic cell death (ICD) of tumor cells with a significant extracellular release or expression of ICD molecules, including high mobility group box 1 protein (HMGB1), calreticulin (CRT), and adenosine triphosphate (ATP). Finally, we show that local intra-tumoral delivery of XAV-Nps during conjunctival melanoma progression significantly suppresses tumor size and conjunctival melanoma progression compared to Con-Nps-treated animals. Collectively, our data suggest that selective inhibition of β-catenin in tumor cells using nanoparticle-based targeted delivery represents a novel approach to suppress tumor progression through increased tumor cell ICD.