Activation of p53 by chemotherapeutic agents enhances reovirus oncolysis.
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.
Department of Microbiology and Immunology, Dalhousie University, Halifax, Canada.
Da
D
Pan
Paola
P
Marcato
Dae-Gyun
DG
Ahn
Shashi
S
Gujar
Lu-Zhe
LZ
Pan
Maya
M
Shmulevitz
Patrick W K
PW
Lee
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D003131:Combined Modality Therapy / Q000379:methods*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D003609:Dactinomycin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005047:Etoposide / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D050504:Oncolytic Viruses / Q000502:physiology*; D012087:Reoviridae / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D000970:Antineoplastic Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016328:NF-kappa B; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D003609:Dactinomycin; D005047:Etoposide