Mre11 inhibition by oncolytic adenovirus associates with autophagy and underlies synergy with ionizing radiation

Abstract

New treatment approaches are needed for hormone refractory prostate cancer. Oncolytic adenoviruses are promising anti-cancer agents, and their efficacy can be improved by combining with conventional therapies such as ionizing radiation. The aim of this study was to determine the timing of oncolytic adenovirus treatment with regard to radiation and study the mechanisms of synergy in combination treatment. Prostate cancer cells were infected with oncolytic adenoviruses, irradiated and synergy mechanisms were assessed. In vivo models of combination treatment were tested. Radiation and oncolytic viruses were synergistic when viral infection was scheduled 24 hr after irradiation. Combination of oncolytic adenovirus with radiotherapy significantly increased antitumor efficacy in vivo compared to either agent alone. Microarray analysis showed dysregulated pathways including cell cycle, mTOR and antigen processing pathways. Functional analysis showed that adenoviral infection was accompanied with degradation of proteins involved in DNA break repair. Mre11 was degraded for subsequent inactivation of Chk2-Thr68 in combination treated cells, while cH2AX-Ser139 was elevated implicating the persistence of DNA double strand breaks. Increased autophagocytosis was seen in combination treated cells. Combination treatment did not increase apoptosis or virus replication. The results provide evidence of the antitumor efficacy of combining oncolytic adenoviruses with irradiation as a therapeutic strategy for the treatment of prostate cancer. Further, these findings propose a molecular mechanism that may be important in radiation induced cell death, autophagy and viral cytopathic effect. ' 2009 UICC

Syngeneic Syrian hamster tumors feature tumor-infiltrating lymphocytes allowing adoptive cell therapy enhanced by oncolytic adenovirus in a replication permissive setting

“…Previous research has shown that oncolytic adenoviruses can be successfully combined with more conventional cancer treatments i.e., chemotherapy 28 and radiotherapy. 29 Further studies are needed to elucidate the underlying mechanism behind the increased efficacy of the combination of TIL and oncolytic adenovirus in vitro. Superior tumor cell killing with the combination of CAR T-cells and Ad5-D24 was recently reported to be associated with accelerated caspase pathways in human tumor cells.…”

Ubenimex enhances the radiosensitivity of renal cell carcinoma cells by inducing autophagic cell death

“…Therefore, autophagy is a decisive factor between cell death and survival, and can be either protective or lead to autophagic cell death. Notably, the induction of autophagy enhances the effects of radiation (15)(16)(17)(18)(19)(20)(21)(22). However, the contribution of autophagy to radiation efficacy remains unclear, particularly in RCC.…”

Adenoviral E4orf3 and E4orf6 Proteins, But Not E1B55K, Increase Killing of Cancer Cells by Radiotherapy in vivo

“…Infection with recombinant adenoviruses expressing E4orf6, E4orf3, and E1B55K 24 h before irradiation significantly increases cell killing in vitro Radiation doses were selected according to relative sensitivity to radiation of each cell line (9,18). RT alone or combined with replication-deficient control virus Ad5(GL) did not affect cell viability at treatment with 8 Gy (Fig.…”

“…Whole-body irradiation was used for the mice to avoid the need for anesthesia. For cell lines, in vitro radiation doses were chosen according to the relative sensitivity of each cell line, respectively (9,18).…”

“…Moreover, radiosensitization potential has been proposed for innate adenoviral gene products early region 1B 55-kDa (E1B55K), early region 4 11-kDa (E4orf3), and 34-kDa (E4orf6) (6)(7)(8)(9). These proteins maintain effective replication of wild-type adenovirus in host cells by preventing cell cycle arrest in response to the presence of linear double-stranded adenovirus genomes, which the cell can interpret as DNA double-strand breaks (DSB) (10).…”