Oncolytic herpes simplex virus and temozolomide synergistically inhibit breast cancer cell tumorigenesis in vitro and in vivo

摘要

The oncolytic herpes simplex virus (HSV) G47 Delta can selectively eliminate glioblastoma cells via viral replication and temozolomide (TMZ) has been clinically used to treat glioblastoma. However, the combined effect of G47 Delta and TMZ on cancer cells, particularly on breast cancer cells, remains largely unknown. The objective of the present study was to investigate the role and underlying mechanism of G47 Delta and TMZ, in combination, in breast cancer cell tumorigenesis. The human breast cancer cell lines SK-BR-3 and MDA-MB-468 were treated with G47 Delta and TMZ individually or in combination. Cell viability, flow cytometry, reverse transcription quantitative-PCR and western blotting were performed to investigate the synergy between G47 Delta and TMZ in regulating breast cancer cell behavior in vitro. The role of G47 Delta and TMZ in suppressing tumorigenesis in vivo was investigated in a xenograft mouse model. G47 Delta and TMZ served a synergistic role resulting in decreased breast cancer cell viability, induction of cell cycle arrest, promotion of tumor cell apoptosis and enhancement of DNA damage response in vitro. The combined administration of G47 Delta and TMZ also effectively suppressed breast cancer cell-derived tumor growth in vivo, compared with the administration of G47 Delta or TMZ alone. Synergy between G47 Delta and TMZ was at least partially mediated via TMZ-induced acceleration of G47 Delta replication, and such a synergy in breast cancer cells in vitro and in vivo provides novel insight into the future development of a therapeutic strategy against breast cancer.