Pre- and post-initiation chemoprevention activity of 2-alkyl/aryl selenazolidine-4(R)-carboxylic acids against tobacco-derived nitrosamine (NNK)-induced lung tumors in the A/J mouse

Abstract

The efficacy of a series of 2-aryl/alkyl selenazolidine-4(R)-carboxylic acids (SCAs) in reducing NNK [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone]-induced lung adenomas in female A/J mice, a model for tobacco-related lung tumorigenesis, has been investigated. With selenazolidines in the diet for 1 month prior to carcinogen administration and during the subsequent 4 months of tumor development, 2-butylSCA, 2-cyclohexylSCA, 2-phenylSCA and 2-oxoSCA were chemopreventive, significantly reducing mean lung tumor numbers from the 10.9 of unsupplemented controls to 4.7, 5.3, 2.8 and 4.7, respectively. When selenazolidine supplementation began three days after carcinogen administration (i.e., post-initiation), 2-butylSCA, 2-cyclohexylSCA, and 2-oxoSCA were chemopreventive. In both regimens, selenocystine was also chemopreventive. In the post-initiation protocol, but with intervention at a precancerous stage (13 days), whole genome expression analysis of lung RNA identified six gene transcripts that weakly correlated with the efficacy of tumor reduction by the four selenocompounds at 4 months. None of these genes were among those identified to be influenced by chemopreventive selenium compounds in human lung cancer cell lines. When supplementation was for 1 month-prior until 3 days-after carcinogen administration, 2-butylSCA, and 2-phenylSCA were chemopreventive but selenocystine was ineffective. Both 2-butylSCA and 2-phenylSCA retained their chemopreventive activity (44% and 40% tumor number reduction, respectively), when the supplementation was shortened and restricted to a pre-initiation period (days -9 to -2). With supplementation spanning 2 days-prior until 3 days-after NNK, reductions in tumor numbers by 2-phenylSCA (26%) and 2-butylSCA (17%) did not achieve statistical significance. Thus, several 2-aryl/alkyl selenazolidines possess chemopreventive activity against NNK-induced lung tumors, and variously demonstrate pre-initiation and post-initiation efficacy.

Figure 1

Structure of selenium compounds evaluated for chemopreventive activity.

Figure 2. Selenium supplementation regimens

NNK administration is designated as day 0. Periods of dietary supplementation with selenocompounds are shown shaded. The regimens are keyed to the tables and figures in which the outcomes of supplementation can be found.

Figure 3. Heat maps depicting the gene expression profiles of mice injected with NNK and provided with selenium-supplemented diets

Treatment groups are indicated across the top; 2-butylSCA (BSCA), 2-oxoSCA (OSCA), 2-cyclohexylSCA (CHSCA), and selenocystine (Se-cystine). The accepted gene symbols are listed on the right and the genes are clustered such that genes with more similar profiles as measure by Euclidean distance in gene space are closer to each other. The scale for gene expression is in log₂ and is shown at the bottom (the maximum and minimum display a 2-fold change). Panel A depicts the gene profiles that best matched the efficacy of tumor reduction of the selenocompounds. Panel B depicts those genes that best discriminate the selenocompounds treatments from the NNK treatment from among the selenocompound-responsive genes identified by others in lung tumor cell lines; methylseleninic acid responsive in H520 cells [25], 1,4-phenylenebis-(methylene)selenocyanate responsive in H460 cells [26].