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Abstract
Mammalian reovirus is a benign virus that possesses the natural ability to preferentially infect and kill cancer cells (reovirus oncolysis). Reovirus exploits aberrant Ras signalling in many human cancers to promote its own replication and spread. In vitro and in vivo studies using reovirus either singly or in combination with anti-cancer drugs have shown very encouraging results. Presently, a number of reovirus combination therapies are undergoing clinical trials for a variety of cancers. Previously we showed that accumulation of the tumor suppressor protein p53 by Nutlin-3a (a specific p53 stabilizer) enhanced reovirus-induced apoptosis, and resulted in significantly higher levels of reovirus dissemination. In this study, we examined the role of p53 in combination therapies involving reovirus and chemotherapeutic drugs. We showed that sub-lethal concentrations of traditional chemotherapy drugs actinomycin D or etoposide, but not doxorubicin, enhanced reovirus-induced apoptosis in a p53-dependent manner. Furthermore, NF-κB activation and expression of p53-target genes (p21 and bax) were important for the p53-dependent enhancement of cell death. Our results show that p53 status affects the efficacy of combination therapy involving reovirus. Choosing the right combination partner for reovirus and a low dosage of the drug may help to both enhance reovirus-induced cancer elimination and reduce drug toxicity.
Highlights
Mammalian reovirus is a benign virus that preferentially replicates in cancer cells while sparing normal cells [1,2]
We previously showed that Nutlin-3a, a specific p53 stabilizer, enhanced reovirus-induced cancer cell death [23]
It was interesting to determine whether the p53 status in cancer cells affects the outcomes of treatments that involve reovirus combined with traditional anti-cancer drugs
Summary
Mammalian reovirus is a benign virus that preferentially replicates in cancer cells while sparing normal cells (reovirus oncolysis) [1,2]. Cancer cells harboring aberrant Ras-signaling pathways have been shown to promote reovirus (Strain T3D) infection and virus spread by affecting various steps of the reovirus replication cycle [3,4,5,6]. Reovirus (ReolysinTM) is undergoing phase II/III clinical trials as a single therapy or combination therapy with various chemotherapy drugs. These studies showed low toxicity profile of reovirus and patients’ partial to complete response to reovirus [8,10,11,20,21], suggesting that reovirus is a promising alternative cancer therapy
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