Destroying c-jun Messenger: new insights into biological mechanisms of DNAzyme function.
The study by Cai and co-workers provided novel insights into the mechanism of action of DNAzymes. Dz13 rendered c-jun mRNA unstable, reduced growth factor expression and increased apoptosis in the tumors without apparent induction of oxidative stress. Interestingly, Dz13-mediated tumor decay was more profound in immunocompetent mice syngeneic to the tumor compared with immunocompromised animals. Immunohistological inspection revealed increased immune and inflammatory cells in Dz13-treated tumors in the immunocompetent mice. In addition, Dz13 mediated tumor regression was prevented by the administration of CD4 or CD8 antibodies, which depleted the mice of the respective T cell subsets. Thus, inhibition of tumor growth by a DNAzyme involves the induction of tumor immunity. These findings suggest that c-Jun inhibition in tumors stimulates apoptosis and adaptive immune mechanisms that attack the tumor. Underpinned by a favorable preclinical safety profile, DNAzymes could provide a new treatment option combining both direct and indirect mechanisms to prevent the growth and spread of non-melanoma skin cancer.
Levon M
LM
Khachigian
Hong
H
Cai
Fergal J
FJ
Moloney
Christopher R
CR
Parish
Beng H
BH
Chong
Roland
R
Stocker
Ross St C
RS
Barnetson
Gary M
GM
Halliday
D000818:Animals; D021881:DNA, Catalytic / Q000627:therapeutic use*; D006801:Humans; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics*; D012878:Skin Neoplasms / Q000188:drug therapy*
D021881:DNA, Catalytic; D016755:Proto-Oncogene Proteins c-jun