Abstract
BACKGROUND AND OBJECTIVE: Short term fasting has been shown to enhance efficacy of chemotherapy by sensitizing tumor cells and protecting normal cells in a variety of cancer models including glioblastoma (GBM). Malignant cells, unlike normal cells, respond to fasting by promoting oncogenic signaling and protein synthesis, which could in turn sensitize them to anti-cancer agents, broadening therapeutic window. We hypothesize that fasting increases replication of oncolytic herpes simplex virus (oHSV) and its oncolytic activity in glioblastoma. MATERIALS AND METHODS: Patient-derived GBM cell lines, MGG8F and MGG29F, were subjected to transient fasting by switching culture medium [DMEM (4.5 g/L of glucose) supplemented with 10% fetal calf serum (FCS)] to DMEM with low glucose (0.5 g/L) and 1% FCS. oHSV G47Δ [ϒ34.5(-), ICP6 (-), LacZ (+), α47 (-)], currently tested in a phase I/II trial for recurrent GBM, and its derivative G47Δ-US11fluc, expressing firefly luciferase driven by the late US11 promoter, were used to investigate the impacts of short term fasting on late HSV gene expression, virus yields and tumor cell killing. RESULTS: 24-hour fasting followed by 24-hour recovery with regular medium increased luciferase expression after G47Δ-US11fluc infection of MGG8F and MGG29F cells. Transient fasting mediated 2-3-fold increase in G47Δ yields in both GBM cells, but not in normal human astrocytes. Although transient fasting alone did not alter cell growth, it significantly enhanced G47Δ killing of GBM cells in vitro. In vivo, 48-hour food restriction doubled luciferase activity and caused no toxicity when G47Δ-US11fluc was intratumorally injected in orthotopic MGG8F xenografts. CONCLUSION: Transient fasting increased viral replication of G47Δ and strengthened its oncolytic activity in GBM cells. These results suggest that transient fasting may be effectively combined to enhance oncolytic HSV therapy of GBM.
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