Contributed by Webster K. Cavenee, May 24, 2017 (sent for review January 18, 2017; reviewed by Raymond Bergan and Samuel D. Rabkin)
Although oncolytic therapy is showing great potential in clinical trials, not all patients benefit from it. Combining oncolytic viruses with anticancer chemicals could provide a better chance to increase the response rate. Here, we report that the combination of an alphavirus (M1) that we identified previously and second mitochondria-derived activator of caspases (Smac) mimetic compounds (SMCs) shows substantial oncolytic effect in vitro, in vivo, and ex vivo (samples from patients’ tumor tissues). The combined effect is mediated by a bystander killing effect and increased replication of M1. Our work provides an example for potentiating the response rate in refractory samples by synergizing oncolytic virus with other anticancer chemicals. We predict that this treatment strategy will be a promising tool to combat cancer in the future.
Oncolytic virotherapy is a treatment modality that uses native or genetically modified viruses that selectively replicate in and kill tumor cells. Viruses represent a type of pathogen-associated molecular pattern and thereby induce the up-regulation of dozens of cytokines via activating the host innate immune system. Second mitochondria-derived activator of caspases (Smac) mimetic compounds (SMCs), which antagonize the function of inhibitor of apoptosis proteins (IAPs) and induce apoptosis, sensitize tumor cells to multiple cytokines. Therefore, we sought to determine whether SMCs sensitize tumor cells to cytokines induced by the oncolytic M1 virus, thus enhancing a bystander killing effect. Here, we report that SMCs potentiate the oncolytic effect of M1 in vitro, in vivo, and ex vivo. This strengthened oncolytic efficacy resulted from the enhanced bystander killing effect caused by the M1 virus via cytokine induction. Through a microarray analysis and subsequent validation using recombinant cytokines, we identified IL-8, IL-1A, and TRAIL as the key cytokines in the bystander killing effect. Furthermore, SMCs increased the replication of M1, and the accumulation of virus protein induced irreversible endoplasmic reticulum stress- and c-Jun N-terminal kinase–mediated apoptosis. Nevertheless, the combined treatment with M1 and SMCs had little effect on normal and human primary cells. Because SMCs selectively and significantly enhance the bystander killing effect and the replication of oncolytic virus M1 specifically in cancer cells, this combined treatment may represent a promising therapeutic strategy.
↵1J.C. and Y.L. contributed equally to this work.
Author contributions: J.C., Y.L., and G.Y. designed research; H.Z., J.L., and Y.T. performed research; J.C., Y.L., W.K.C., and G.Y. analyzed data; and J.C., Y.L., W.K.C., and G.Y. wrote the paper.
Reviewers: R.B., Oregon Health Sciences University; and S.D.R., Massachusetts General Hospital and Harvard Medical School.
The authors declare no conflict of interest.
Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, https://www.ncbi.nlm.nih.gov/geo (accession no. GSE92918).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1701002114/-/DCSupplemental.
