Transient fasting enhances replication of oncolytic herpes simplex virus in glioblastoma

Short-term nutritional restriction (fasting) has been shown to enhance the efficacy of chemotherapy by sensitizing cancer cells and protecting normal cells in a variety of cancer models, including glioblastoma (GBM). Cancer cells, unlike normal cells, respond to fasting by promoting oncogenic signaling and protein synthesis. We hypothesized that fasting would increase the replication of oncolytic herpes simplex virus (oHSV) in GBM. Patient-derived GBM cell lines were fasted by growth in glucose and fetal calf serum restricted culture medium. "Transient fasting", 24-hour fasting followed by 24-hour recovery in complete medium, increased late virus gene expression and G47 Delta yields about 2-fold in GBM cells, but not in human astrocytes, and enhanced G47 Delta killing of GBM cells. Mechanistically, "transient fasting" suppressed phosphorylation of the subunit of eukaryotic initiation factor 2 alpha (eIF2 alpha) and c-Jun N-terminal kinases (JNK) in GBM cells, but not in astrocytes. Pharmacological inhibition of JNK also increased G47 Delta yield. In vivo, transient fasting (48-hour food restriction and 24-hour recovery) doubled luciferase activity after intratumoral G47 Delta-US11fluc injection into orthotopic GBM xenografts. Thus, "transient fasting" increases G47 Delta replication and oncolytic activity in human GBM cells. These results suggest that "transient fasting" may be effectively combined to enhance oncolytic HSV therapy of GBM.