Lung cancer causes over one million deaths per year worldwide and cigarette smoking, the proximate cause, results in a field cancerization of the respiratory track. Lung cancer cells or premalignant cells may be susceptible to apoptosis or necrosis-inducing agents. Statins inhibit the acetyl coenzyme A pathway reducing L-mevalonate that is a precursor to isoprenoids necessary for post-translational processing, resulting in apoptosis. Lovastatin was added to four lung cancer cell lines and normal human bronchial epithelial cells followed by Western blots to evaluate proteins in the cell cycle, oxidant, and apoptotic pathways. Flow cytometry revealed significant increases in three of four lung cancer cell lines in apoptosis and necrosis after lovastatin treatment at 10 microM for 72 h. Lovastatin adversely affected lung cancer cell survival with increases in cell-cycle check-point inhibitors p21WAF and/or p27KIP and a decrease in cyclin D1. All four lung cancer cell lines had a decrease in glutathione after lovastatin treatment consistent with reduced protection against reactive oxidant species. Three of four lung cancer cell lines had increased cytochrome c release with reduced pro-caspase-3 and increases in activated caspase-3. Lovastatin induces apoptosis and necrosis in lung cancer cell lines by causing alterations in the cell cycle, reducing glutathione, and activating p53, Bax protein, and caspases while increasing cytochrome c in apoptosis pathways. Targeting HMG-CoA reductase may represent an approach to lung cancer chemotherapy, e.g., reversing ground glass opacities detected on CT scans or resolving airway preneoplasias detected by bronchoscopy before they progress to malignant transformation.