Temozolomide resistant human brain tumor stem cells are susceptible to recombinant vesicular stomatitis virus and double-deleted Vaccinia virus in vitro

Background: Malignant glioma still has a poor prognosis and remains incurable. Although temozolomide (TMZ) has demonstrated antitumor activity, its use recently has been halted because of some patients' resistance to this drug. New treatments are desperately needed. An oncolytic virus (virotherapy) is being developed as a novel cancer therapy. We have previously reported that recombinant Vesicular Stomatitis Virus (VSV-Delta M51) and double deleted Vaccinia Virus (vvDD) infected and killed glioma cell lines in vitro and prolonged survival in animal glioma models. As a proposed ex vivo test, the oncolytic potential of VSV-Delta M51 and vvDD in the established human brain tumor stem cells (BTSCs) and the differentiated cells from fresh brain tumor tissues in vitro were further investigated. Methods: BTSCs from fresh surgical glioblastoma multiforme (GBM) specimens were isolated and cultured, and the characterization of BTSCs were tested. The sensitivity of BTSCs to TMZ and the susceptibility of TMZ resistant BTSCs and their differentiated cells to both oncolytic viruses were examined. Results: The BTSC spheres cultured had all the characteristics of stem cells. The GFP-labeled VSV-Delta M51 and vvDD could infect TMZ resistant BTSCs and cause cytopathic effects. The VSV-Delta M51 and vvDD inhibited the self-renewal activity of TMZ resistant BTSCs. And the VSV-Delta M51 and vvDD also infected and caused cytopathic effects in differentiated BTSCs. Conclusion: VSV-Delta M51and vvDD could infect and kill both the TMZ resistant BTSCs and the differentiated compartments of GBMs in vitro, suggesting that they may be an effective treatment supplement for GBM therapy, particularly for TMZ resistant GBM patients.