Abstract
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.
Highlights
The c-jun gene is mapped to 1p32-p31 and encodes the 45kDa bZIP-domain-containing transcription factor c-Jun that, in combination with protein partners, forms AP-1
Protein partners of c-Jun are many and include c-Fos, pRb, BRCA1, ATF-2 and ERG. c-Jun/ AP-1 is dynamically regulated by growth factors and cytokines, is overexpressed in a range of cancers including Basal cell carcinoma (BCC), Squamous cell carcinomas (SCC) and melanoma, and stimulates the expression of numerous genes [2,3,4]
The first in vivo demonstration of efficacy was the use of DNAzymes targeting the transcription factor early growth response (Egr)-1 as inhibitors of intimal thickening in a rat model of balloon angioplasty [7]
Summary
Skin cancer is the commonest cancer in lightskinned Caucasians and non-melanoma skin cancer accounts for over 90% of these malignancies [1]. Work by our group and others has demonstrated that immediate-early genes can serve as key targets in a range of cancer types. C-Jun/ AP-1 is dynamically regulated by growth factors and cytokines, is overexpressed in a range of cancers including BCC, SCC and melanoma, and stimulates the expression of numerous genes [2,3,4]. The first in vivo demonstration of efficacy was the use of DNAzymes targeting the transcription factor early growth response (Egr)-1 as inhibitors of intimal thickening in a rat model of balloon angioplasty [7].
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