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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Research Grants (R03)
Project #
1R03CA186233-01
Application #
8704599
Study Section
Special Emphasis Panel ()
Program Officer
Perloff, Marjorie
Project Start
2014-04-10
Project End
2016-03-31
Budget Start
2014-04-10
Budget End
2015-03-31
Support Year
1
Fiscal Year
2014
Total Cost
$75,500
Indirect Cost
$25,500
Name
University of South Alabama
Department
Type
Schools of Medicine
DUNS #
172750234
City
Mobile
State
AL
Country
United States
Zip Code
36688
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
Tyagi, Nikhil; Srivastava, Sanjeev K; Arora, Sumit et al. (2016) Comparative analysis of the relative potential of silver, Zinc-oxide and titanium-dioxide nanoparticles against UVB-induced DNA damage for the prevention of skin carcinogenesis. Cancer Lett 383:53-61
Srivastava, Sanjeev K; Bhardwaj, Arun; Arora, Sumit et al. (2015) MicroRNA-345 induces apoptosis in pancreatic cancer cells through potentiation of caspase-dependent and -independent pathways. Br J Cancer 113:660-8
Srivastava, S K; Bhardwaj, A; Arora, S et al. (2015) Interleukin-8 is a key mediator of FKBP51-induced melanoma growth, angiogenesis and metastasis. Br J Cancer 112:1772-81
Arora, Sumit; Tyagi, Nikhil; Bhardwaj, Arun et al. (2015) Silver nanoparticles protect human keratinocytes against UVB radiation-induced DNA damage and apoptosis: potential for prevention of skin carcinogenesis. Nanomedicine 11:1265-75
Deshmukh, Sachin K; Srivastava, Sanjeev K; Bhardwaj, Arun et al. (2015) Resistin and interleukin-6 exhibit racially-disparate expression in breast cancer patients, display molecular association and promote growth and aggressiveness of tumor cells through STAT3 activation. Oncotarget 6:11231-41
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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