Enhanced tumor cell kill by combined treatment with a small-molecule antagonist of mouse double minute 2 and adenoviruses encoding p53.
Strategies to treat cancer by restoring p53 tumor suppressor functions are being actively investigated. These approaches range from expressing an exogenous p53 gene in p53 mutant cancers to antagonizing a p53 inhibitor in p53 wild-type (WT) cancer cells. In addition, exogenous p53 is used to strengthen the anticancer efficacy of oncolytic adenoviruses. Many cancers express high levels of the major negative regulator of p53, mouse double minute 2 (MDM2) protein. Recently, a novel class of highly potent and specific MDM2 antagonists, the Nutlins, was identified. We envisioned that Nutlins could protect both endogenous and exogenous p53 from MDM2-mediated inactivation. We therefore investigated treating human cancer cells with a combination of adenovirus-mediated p53 gene therapy and Nutlin. Combination treatment resulted in broadly effective cell kill of p53 WT and p53-negative cancer cells. Cytotoxicity was associated with profound cell cycle checkpoint activation and apoptosis induction. We also tested Nutlin in combination with oncolytic adenoviruses. Nutlin treatment accelerated viral progeny burst from oncolytic adenovirus-infected cancer cells and caused an estimated 10- to 1,000-fold augmented eradication of p53 WT cancer cells. These findings suggest that Nutlins are promising compounds to be combined with p53 gene therapy and oncolytic virotherapy for cancer.
Graat
Harm C A
HC
Department of Medical Oncology, VU University Medical Center, PO Box 7057, 1007 MB, Amsterdam, the Netherlands.
Carette
Jan E
JE
Schagen
Frederik H E
FH
Vassilev
Lyubomir T
LT
Gerritsen
Winald R
WR
Kaspers
Gertjan J L
GJ
Wuisman
Paul I J M
PI
van Beusechem
Victor W
VW
D000256:Adenoviridae / Q000235:genetics*; D017209:Apoptosis; D002452:Cell Count; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D016158:Genes, p53; D005838:Genotype; D006801:Humans; D007093:Imidazoles / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology* / Q000628:therapy; D050504:Oncolytic Viruses / Q000378:metabolism; D010879:Piperazines / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D007093:Imidazoles; D010879:Piperazines; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2