Plumbagin Reduces Proliferation and Survival of Non-Small Cell Lung Carcinoma Irrespective of Gefitinib Resistance

Abstract

Plumbagin is a naturally derived naphthoquinone phytochemical which exhibits promising medicinal properties, including anticancer activities. In the present study, the anticancer potential of plumbagin has been demonstrated in human lung cancer cells A549, NCI-H522 and gefitinib resistant A549 cells (A549/GR). Plumbagin showed impressive cytotoxic, anti-proliferative, and anti-migratory activities against A549, NCI-H522 and A549/GR cells. Plumbagin treatment significantly reduced the size of A549 tumor spheroids in a concentration-dependent manner. Plumbagin also induced S and G2/M phase arrest of gefitinib sensitive and resistant lung cancer cells. Upon plumbagin treatment, reactive oxygen species (ROS) content of the lung cancer cells escalated and reduced the mitochondrial membrane potential, which triggers caspase-dependent apoptosis. Interestingly, ROS scavenger N-acetylcysteine (NAC) inhibited the plumbagin induced apoptosis in lung cancer cells. Expression of antioxidant genes such as glutathione S-transferase P1 and superoxide dismutase-2 were found to be upregulated with plumbagin treatment in A549 cells. Plumbagin affected the expression of intrinsic apoptotic pathway proteins in A549 and A549/GR cells. Increased expression of cytochrome c promotes the activation of pro-apoptotic protein Bax with decreased expression of anti-apoptotic protein Bcl-2. Further, plumbagin activated the mitochondrial downstream pathway protein caspase-9 and caspase-3 leading to apoptosis of A549 and A549/GR cells. To summarize, our study suggests that plumbagin may be utilized as a future anti-cancer phytotherapeutic agent against lung cancer, which is a major threat owing to its development of drug resistance towards current treatment regimens.