The combination of Reolysin and belinostat results in significantly decreased tumor cell proliferation and augmented apoptosis in parental and belinostat-resistant Karpas-299 tumors. (A-B) Immunohistochemical analysis demonstrates that administration of Reolysin and belinostat effectively decreases PCNA-positive cells (A) and induces significant levels of caspase-3–positive cells (B). Percent PCNA and active caspase-3–positive cells were determined by manual counting. Data are shown as mean ± SD (n = 3 random fields). *P < .05 indicates a significant difference from vehicle or **P < .05 for treatment with either belinostat or Reolysin as a single agent. Scale bars represent 50 μm. (C) Belinostat-induced reduction in STAT1 expression increases TCL cell vulnerability to oncolytic reovirus-mediated cell death. The development of belinostat resistance, acute treatment with belinostat, or STAT1 shRNA infection decreases the expression of STAT1. Oncolytic reovirus replicates significantly more effectively in belinostat-resistant cells and when administered in combination with belinostat resulting in enhanced antilymphoma activity.