Safety profile of sikamat virus and its oncolytic potential in leukemic cells and cancer stem cells
Myelogenous leukaemia remains a global health concern. The oncotherapy resistance of leukaemia might be due to the existence of cancer stem cells population. This study investigated the therapeutic potential of Sikamat virus (PRV7S), a Pteropine orthoreovirus, as an oncolytic virus against acute myeloid leukaemia (AML) and chronic myeloid leukaemia (CML). Using AML and CML cell lines (THP1 and K562) and an AML-M5-derived cancer stem cell (CSC) model, PRV7S was shown to infect, replicate within, and reduce cell viability in these leukaemic cells. PRV7S-induced cell death was associated with caspase-mediated apoptosis without significant cell cycle arrest. Transcriptomic and proteomic analyses revealed that PRV7S infection altered several cell death pathways, including apoptosis and necroptosis, highlighting its complex cell death mechanisms. PRV7S replicated efficiently in infected cells, though it did not cause persistent infection. An in vivo safety evaluation in immunocompetent mice demonstrated that PRV7S was well-tolerated, showing no adverse effects on survival, body weight, or histopathology, and no evidence of viral persistence. These findings suggest PRV7S as a promising oncolytic candidate for myeloid leukaemia, with potential efficacy against CSCs and a favourable safety profile. The study provides new insights into the cellular pathways involved in PRV7S-mediated oncolysis and supports further exploration of PRV7S in clinical applications for resistant leukaemic and solid tumours. Overall design: mRNA-seq profiling of PRV7S infected and non-infected wildtype THP-1 (ATCC TIB-202) and K562 (ATCC CCL-243) cells at Day 5 post-infection.