Redox mechanisms of selenocompounds in lung cancer prevention and treatment

Lung cancer is the most fatal and second most prevalent type of cancer in the United States with a current five-year survival rate of only 16%. Thus, novel therapeutic agents to both prevent and treat lung cancer are necessary. One such agent is selenium, a micronutrient present in the diet. Epidemiological studies and supplementation trials with selenium have shown it to decrease lung cancer incidence and mortality. Selenium has also been shown to decrease lung tumor burden in animal studies, with the benefit being compound dependent. The mechanisms of action of selenium in cancer remain under investigation, but may relate to cellular redox status regulation. The hypothesis of this work is that distinct selenocompounds alter the cellular redox state of human lung cells through the Nrf2/antioxidant response element (ARE) pathway and the antioxidant selenoprotein thioredoxin reductase 1 (TR1). This hypothesis was tested using three specific aims: 1. Determine the redox effects of selenocompounds in A549 adenocarcinoma cells and BEAS-2B nonmalignant bronchial epithelial cells. 2. Investigate the ability of selenocompounds to activate the Nrf2/ARE pathway in nonmalignant BEAS-2B cells. 3. Determine if TR1 modulates the cytotoxcity of selenocompounds in malignant A549 cells. iv Several selenocompounds were investigated, including the selenoamino acids selenomethionine and selenocystine, the selenocysteine prodrugs 2-butyl selenazolidine- 4(R)-carboxylic acid (BSCA) and 2-cyclohexylselenazolidine-4(R)-carboxylic acid (ChSCA), and methylseleninic acid (MSA). This work indicates that selenium can modulate cellular redox status, but the effects are compound and cell-line specific. Selenocystine and ChSCA induced oxidative stress in A549 cells and activated the Nrf2 pathway in BEAS-2B cells. Selenocystine, ChSCA and BSCA also demonstrated enhanced cytotoxicity in A549 cells with TR1 knockdown, which was related to their ability to deplete intracellular glutathione. MSA produced a reductive stress in A549 cells and activated the Nrf2 pathway in BEAS-2B cells, but its cytotoxicity was not altered by TR1 status. Selenomethionine failed to modulate cellular redox status, activate the Nrf2 pathway, or demonstrate enhanced cytotoxicity with TR1 knockdown. These findings further demonstrate that selenium has compound-dependent redox effects and certain compounds, namely selenocystine and ChSCA, may have actions as both cancer preventive and anti-tumor agents in the lung.