Plumbagin (5-hydroxy-2-methyl-1, 4-naphthoquinone) occurs naturally in the herb Plumbago zeylanica L., which has been safely used for centuries in Indian Ayurvedic and traditional oriental medicine practices for the treatment of various ailments, including rheumatoid arthritis, acne, and microbial infections. Plumbagin has attracted a great deal of research interest due to its diverse pharmacological effects. The known pharmacological effects of plumbagin or Plumbago zeylanica extract include anti-leishmanial, anti-bacterial, anti-fungal, anti-allergic, hypolipidaemic, anti-atherosclerotic, and anticancer effects. For instance, dietary feeding of 200 ppm plumbagin decreased the incidence and multiplicity of azoxymethane-induced intestinal carcinogenesis in rats. We now demonstrate that plumbagin suppresses growth of cultured human prostate cancer cells (PC-3, LNCaP, and C4-2) irrespective of their androgen responsiveness or p53 status. The viability of each cell line was decreased significantly by treatment with plumbagin at pharmacologically relevant concentrations. Contrary to previous reports, plumbagin-mediated decrease in prostate cancer cell viability was not due to perturbations in cell cycle progression. Instead, plumbagin-mediated decrease in cell viability correlated with apoptosis induction characterized by appearance of sub-diploid apoptotic fraction and release of histone-associated DNA fragments into the cytosol. The plumbagin-induced apoptosis was associated with generation of reactive oxygen species (ROS) and depletion of intracellular glutathione levels. Pretreatment of cells with antioxidants inhibited plumbagin-mediated ROS generation as well as release of histone-associated DNA fragments into the cytosol. Plumbagin treatment also resulted in alteration of expression of genes responsible for ROS metabolism, including superoxide dismutase 2 (Mn-SOD) as revealed by RT2 Superarray analyses. Activity and protein levels of Mn-SOD were reduced by treatment with plumbagin in a dose-dependent manner. In conclusion, the present study reveals that the plumbagin-induced apoptosis in human prostate cancer cells is mediated by modulation of cellular redox status and ROS generation (supported in part by NCI grant CA115498).
99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA