Differential Susceptibility of Nonmalignant Human Breast Epithelial Cells and Breast Cancer Cells to Thiol Antioxidant-Induced G1-Delay

• DOI: 10.1089/ars.2005.7.711
• Publication Date: 2005-05-12T17:56:31Z
• Authors: Sarita G. Menon; Mitchell C. Coleman; Susan A. Walsh; Douglas R. Spitz; Prabhat C. Goswami
• Keywords: 0301 basic medicine; 0303 health sciences; G1 Phase; Breast Neoplasms; Cell Cycle Proteins; Epithelial Cells; Antioxidants; Acetylcysteine; Cell Line; 3. Good health; 03 medical and health sciences; Humans; Breast; Sulfhydryl Compounds; Oxidation-Reduction

Reactive oxygen species (ROS) and ROS signaling have been implicated in a variety of human pathophysiological conditions that involve aberrant cellular proliferation, particularly cancer. We hypothesize that intracellular redox state differentially affects cell-cycle progression in nonmalignant versus malignant cells. The thiol antioxidant, N-acetyl-L-cysteine (NAC), was used to alter intracellular redox state in nonmalignant human breast epithelial (MCF-10A) and breast cancer cells (MCF-7 and MDA-MB-231). Treatment of cells with NAC resulted in significant augmentation of intracellular small-molecular-weight thiols, glutathione and cysteine. In addition, NAC treatment decreased oxidation of a prooxidant-sensitive dye in MCF-10A cells, but not in MDA-MB-231 and MCF-7 cells. NAC-induced shifts in intracellular redox state toward a more reducing environment caused G(1) delays in MCF-10A cells without causing any significant changes in MCF-7 and MDA-MB-231 cell-cycle progression. NAC treatment of MCF-10A (but not MCF-7 and MDA-MB-231) was accompanied by a decrease in cyclin D1 and an increase in p27 protein levels, which correlated with increased retinoblastoma protein hypophosphorylation. These results show differential redox control of progression from G(1) to S in nonmalignant versus malignant cells and support the hypothesis that loss of a redox control of the cell cycle could contribute to aberrant proliferation seen in cancer cells.