Each year, there are more new cases of skin cancer than the combined incidence of breast, prostate, lung and colon cancers, which clearly emphasizes the need for the development of effective prevention strategies. Ultraviolet (UV) radiation from sun, particularly its UVB component, is the most established epidemiological cause of skin cancer. UVB radiation causes DNA damage, which if remained unrepaired ultimately leads to accumulation of carcinogenic mutations and subsequent malignant transformation. Currently, several topical sunscreen formulations are being used for protection against UV radiation-induced skin injury and carcinogenesis;however, none seem to be very much effective and incidence of skin cancer continues to rise every coming year. This proposal is based on our novel findings demonstrating that the pretreatment of human immortalized keratinocytes (HaCaT) with silver nanoparticles (AgNPs): i) leads to reduced formation of cyclobutane pyrimidine dimers (CPDs) upon exposure to UVB radiation, ii) protects the HaCaT keratinocytes from UVB radiation-induced apoptosis, iii) suppresses basal as well as UVB-induced ROS production, and iv) induces cell cycle arrest in G1/S phase. Based on these promising findings, we hypothesize that Silver nanoparticles (AgNPs) are effective chemopreventive agents against UVB-induced skin injury and carcinogenesis. The overall objective of this pilot proposal is to generate additional supportive data towards this hypothesis using biochemical and functional assays, which would provide strong support for the design of rigorous studies to explore the chemopreventive potential of AgNPs. Thus, we propose two complementary Specific Aims: 1) Define the molecular mechanisms underlying chemoprotective effects of silver nanoparticles against UVB radiation-induced skin carcinogenesis, and 2) Evaluate the chemoprotective efficacy of silver nanoparticles against UVB-induced skin carcinogenesis in mouse model. Studies proposed in Aim 1 will provide us mechanistic insight into the chemoprotective action of AgNPs against UVB-induced skin carcinogenesis, while those proposed in Aim 2 will provide direct pre-clinical evidence for chemoprotective efficacy of AgNPs. The outcome from the proposed pilot studies will form the bases for future investigations to develop AgNPs-based effective chemopreventive formulation(s).

Public Health Relevance

Chronic exposure of the skin to solar ultraviolet (UV) radiation induces multiple adverse effects and poses significant risk for skin cancer development. In the current proposal, we will investigate the chemopreventive efficacy of silver nanoparticles (AgNPs) against UVB radiation- induced skin carcinogenesis using in vitro and in vivo (SKH1 hairless mouse model), and delineate underlying molecular mechanisms. Successful completion of the proposed studies will provide strongly supportive preliminary data to explore the preventive efficacy of AgNPs, and may ultimately lead to the generation of novel and effective chemopreventive approaches against UVB radiation-induced skin carcinogenesis.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Small Research Grants (R03)
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Perloff, Marjorie
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University of South Alabama
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Tyagi, Nikhil; Arora, Sumit; Deshmukh, Sachin K et al. (2016) Exploiting Nanotechnology for the Development of MicroRNA-Based Cancer Therapeutics. J Biomed Nanotechnol 12:28-42
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Khan, Mohammad Aslam; Srivastava, Sanjeev K; Bhardwaj, Arun et al. (2015) Gemcitabine triggers angiogenesis-promoting molecular signals in pancreatic cancer cells: Therapeutic implications. Oncotarget 6:39140-50
Tyagi, Nikhil; Bhardwaj, Arun; Srivastava, Sanjeev K et al. (2015) Development and Characterization of a Novel in vitro Progression Model for UVB-Induced Skin Carcinogenesis. Sci Rep 5:13894
Palanki, Rohan; Arora, Sumit; Tyagi, Nikhil et al. (2015) Size is an essential parameter in governing the UVB-protective efficacy of silver nanoparticles in human keratinocytes. BMC Cancer 15:636
Bhardwaj, Arun; Srivastava, Sanjeev K; Singh, Seema et al. (2014) CXCL12/CXCR4 signaling counteracts docetaxel-induced microtubule stabilization via p21-activated kinase 4-dependent activation of LIM domain kinase 1. Oncotarget 5:11490-500

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