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Kathryn E. Klump, Svetlana V. Kiosseva, Sudipta Seal, Michael A. Dyer, James F. McGinnis; Therapeutic Inhibition Of Retinoblastoma By Nanoceria. Invest. Ophthalmol. Vis. Sci. 2012;53(14):6549.
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Retinoblastoma is a cancer of the developing retina that initiates during fetal development. In a separate unpublished study, we have found that retinoblastomas are under oxidative stress accompanied by the production of reactive oxygen species (ROS) (M.A.D., unpublished). Spontaneous production of ROS by malignant cells can associate with upregulation of vascular endothelial growth factor (VEGF) and initiation of angiogenesis, which sustains tumor growth. Nanoceria are antioxidant cerium oxide nanoparticles unique in their ability to regeneratively and catalytically scavenge ROS. When engineered into nanoparticles 3-5nm in size, nanoceria are characterized by an enhanced surface area to volume ratio and an increased ability to participate in redox reactions mimicking the activity of the endogenous cellular defense mechanisms of superoxide dismutase and catalase. Our lab has previously shown that nanoceria are capable of decreasing ROS and inhibiting neovascularization in an animal model of heritable retinal degeneration. We hypothesize that in vivo treatment with nanoceria during tumorigenesis will result in downregulation of VEGF, inhibition of angiogenesis, and decreased tumor growth in a mouse model of heritable retinoblastoma.
SJRBL-8 cells mouse retinoblastoma cells were incubated with increasing concentrations of nanoceria (1nM-1mM) for 24, 48, and 72 hours to determine whether or not nanoceria affect proliferation of retinoblastoma cells. We also performed intravitreal injections of nanoceria (172 ng/eye) in P53TKO mice (Chx10-cre; Rb Lox/-; p53 Lox/-; P107-/-) following tumor onset. Live animal imaging, histology, and molecular analysis including PCR array were used to assess changes in tumor growth and cytokine signaling.
Our data suggest that nanoceria are effective inhibitory agents in a mouse model of retinoblastoma, resulting in decreased tumor growth in vivo as well as decreased cell proliferation in vitro.
Based on these data we propose that nanoceria represent a novel anti-cancer therapeutic approach which may be effective as a monotherapy or an as an adjunct to standard chemotherapeutic modalities.
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