Abstract
We have demonstrated that oncolytic vaccinia virus synergizes with doxorubicin (DOX) in inducing immunogenic cell death in platinum-resistant ovarian cancer cells and increases survival in syngeneic and xenograft tumor models. However, the mechanisms underlying the virus- and doxorubicin-mediated cancer cell death remain unknown. In this study, we investigated the effect of the oncolytic virus and doxorubicin used alone or in combination on activation of the cytoplasmic transcription factor CREB3L1 (cyclic AMP [cAMP] response element-binding protein 3-like 1) in ovarian cancer cell lines and clinical specimens. We demonstrated that doxorubicin-mediated cell death in ovarian cancer cell lines was associated with nuclear translocation of CREB3L1 and that the effect was augmented by infection with oncolytic vaccinia virus or treatment with recombinant interferon (IFN)-β used as a viral surrogate. This combination treatment was also effective in mediating nuclear translocation of CREB3L1 in cancer cells isolated from ovarian tumor biopsies at different stages of disease progression. The measurement of CREB3L1 expression in clinical specimens of ovarian cancer revealed lack of correlation with the stage of disease progression, suggesting that understanding the mechanisms of nuclear accumulation of CREB3L1 after doxorubicin treatment alone or in combination with oncolytic virotherapy may lead to the development of more effective treatment strategies against ovarian cancer.
Highlights
Ovarian cancer (OC), often known as the silent killer, is the leading cause of death from gynecological malignancies.[1]
We have previously reported that the immunogenic cell death (ICD)-inducing combination treatment consisting of the thymidine kinase (TK)- and vaccinia growth factor (VGF)-deleted strain of the Western Reserve (WR) virus and DOX resulted in synergistic killing of paclitaxel- and carboplatin-resistant murine and human OC cells in vitro and increased survival in tumor-bearing syngeneic mice that was associated with induction of antitumor immunity.[9]
Using an extended panel of human OC cell lines, including SKOV3, A2780, and OVCA429, we investigated the efficacy of the combined oncolytic vaccinia virus (OVV) and DOX treatment on inhibition of cell proliferation
Summary
Ovarian cancer (OC), often known as the silent killer, is the leading cause of death from gynecological malignancies.[1]. The approval of ICD-inducing pegylated liposomal DOX (Doxil) as a major component in the routine management of platinum-resistant epithelial OC (EOC)[8] led to investigation of the combined treatment efficacy of oncolytic vaccinia virus (OVV) and DOX against platinum-resistant murine and human OC cells in syngeneic and xenograft OC models.[9]
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