Curcumin sensitizes lung adenocarcinoma cells to apoptosis via intracellular redox status mediated pathway.

The present study demonstrates that curcumin acts as pro-oxidant and sensitizes human lung adenocarcinoma epithelial cells (A549) to apoptosis via intracellular redox status mediated pathway. Results indicated that curcumin induced cell toxicity (light microscopy and MTT assay) and apoptosis (AnnexinV-FITC/PI labeling and caspase-3 activity) in these cells. These events seem to be mediated through generation of reactive oxygen species (ROS) and superoxide radicals (SOR) and enhanced levels of lipid peroxidation. These changes were accompanied by increase in oxidized glutathione (GSSG), reduced glutathione (GSH) and gamma-glutamylcysteine synthetase (gamma-GCS) activity, but decrease in GSH/GSSG ratio. The induction of apoptosis and decrease in GSH/GSSG ratio was also accompanied by sustained phosphorylation and activation of p38 mitogen activated protein kinase (MAPK). On the other hand, addition of N-acetyl cysteine (NAC), an antioxidant, blocked the curcumin-induced ROS production and rescued malignant cells from curcumin-induced apoptosis through caspase-3 deactivation. However, L-buthionine sulfoximine (BSO), a GSH synthesis blocking agent, further enhanced curcumin-induced ROS production and apoptosis in A549 cells. Decreased GSH/GSSG ratio seems to be a crucial factor for the activation of MAPK signaling cascade by curcumin. The study therefore, provides an insight into the molecular mechanism involved in sensitization of lung adenocarcinoma cells to apoptosis by curcumin.

Cigarette smoke condensate promotes cell proliferation through disturbance in cellular redox homeostasis of transformed lung epithelial type-II cells.

Present study was initiated to evaluate the effects of cigarette smoke condensate (CSC) on the cellular changes at molecular levels in non-small lung carcinoma cells (A549). Cigarette smoke condensate at low concentration (0.1 microg/ml) induced cancer cell proliferation, DNA synthesis, reduced glutathione (GSH) levels and intercellular adhesion molecule-1 (ICAM-1) expression without any significant change in reactive oxygen species (ROS) and superoxide radicals (SOR) production. The increased levels of GSH and ICAM-1 due to increased gamma-glutamylcysteine synthetase (gamma-GCS) activity and transcriptional activation of ICAM-1 gene respectively might be via activation of p38 mitogen activated protein kinase (p38 MAPK). The induction of ICAM-1 expression and cell proliferation reflect the tumor promoting activity of low CSC concentration. On the other hand, high CSC concentration (50 microg/ml), which is doubtful to be achieved in the lungs even in the chain smokers, induced killing effects on cancer cells by increasing apoptosis, ROS and SOR production, inducing cell cycle arrest, and increased ICAM-1 levels. These changes were found to be associated with altered GSH/GSSG ratio which shifted the redox balance towards more oxidizing equivalent followed by activation of p38 MAPK and stress-activated protein kinase (SAPK) involved in signaling cascade and finally transcriptional activation of gamma-GCS and ICAM-1 genes. These changes were found to be p38 and SAPK dependent.