A Novel Agent for Lung Cancer Prevention
Abstract
Lung cancer is the leading cause of cancer related deaths in the United States. Despite the identification of several preventive agents and strategies, optimal prevention of lung cancer, especially in smokers and ex-smokers who are at high risk, has not been achieved. More effective agents are therefore required that would safely achieve prevention without drastic side effects. Novel compounds which are rational modifications of well-established chemopreventive agents and follow a similar mechanism of action, but with enhanced potency, reduced toxicity, and lower dose requirement, may be clinically more relevant. We have developed one such agent p-XS-Asp, designed by conjugating two well known chemopreventive agents i.e. 1,4-phenylenebis(methylene)-selenocyanate (p-XSC) and aspirin, which has shown promising lung cancer preventive properties in our preliminary in vitro and animal studies. The long-term goal of this project is to develop this rationally-designed, effective, and safe agent for the prevention and interception of smoking-related lung cancer. Given the preeminence of tobacco carcinogens in initiating and driving lung cancer, we hypothesize that p-XS-Asp exerts chemopreventive effect at both initiation and post-initiation stages of lung tumorigenesis through (i) inhibition of Phase I carcinogen activation, (ii) induction of Phase II carcinogen detoxification, (iii) suppressing activation of AKT/COX-2 pathways, and (iv) inhibiting proliferation and viability of preneoplastic cells. The specific objectives of this proposal are to (i) test the efficacy of p-XS-Asp for inhibiting lung cancer development at different stages of NNK-induced carcinogenesis using the A/J mouse lung cancer model, (ii) evaluate the pharmacological and biochemical mechanisms by conducting p-XS-Asp metabolism and comparing PK/bioavailability with p-XSC, and (iii) elucidate mechanisms of action(s) of anti-initiation and anti-progression effects of p-XS-Asp.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2020
- Accession Number
- AD1113585
Entities
People
- Arun K Sharma
Organizations
- Pennsylvania State University