Plumbagin, Isolated from Plumbago zeylanica, Induces Cell Death through Apoptosis in Human Pancreatic Cancer Cells

Department of Radiation Oncology, Far Eastern Memorial Hospital, Graduate Institute of Traditional Chinese Medicine, Chang Gung University, Taoyuan, Taiwan.
Pancreatology (Impact Factor: 2.84). 12/2009; 9(6):797-809. DOI: 10.1159/000210028
Source: PubMed


Pancreatic cancer is one of the most resistant malignancies. Several studies have indicated that plumbagin isolated from Plumbago zeylanica possesses anticancer activity. However, its antitumor effects against pancreatic cancer have not been explored.
We investigated the effect of plumbagin on the growth of human pancreatic carcinoma cells and its possible underlying mechanisms.
Plumbagin inhibited the growth of Panc-1 and Bxpc-3 cells in a dose-dependent and time-dependent manner. Liu's staining and transmission electron microscopy demonstrated morphological changes resembling apoptosis in Panc-1 cells treated with plumbagin. The degree of apoptosis was assessed by measuring the proportions of sub-G(1), annexin V+/propidium iodide-, and terminal- deoxynucleotidyl-transferase-mediated-nick-end labeling (TUNEL)+ cells, and a significant increment in apoptotic cells was observed. Exposure to plumbagin caused the upregulation of Bax, a rapid decline in mitochondrial transmembrane potential, apoptosis-inducing factor overexpression in cytosol, and the cleavage of procaspase-9 and poly ADP-ribose polymerase. Activation of caspase-3, but not caspase-8, was evidenced by fluorometric substrate assay. Pretreatment with caspase inhibitors did not block plumbagin-induced apoptosis. Alternatively, it is possible that plumbagin downregulated phosphoinositide 3-kinase activity through a negative feedback mechanism. In an orthotopic pancreatic tumor model, plumbagin markedly inhibited the growth of Panc-1 xenografts without any significant effect on leukocyte counts or body weight.
Plumbagin may induce apoptosis in human pancreatic cancer cells primarily through the mitochondria-related pathway followed by both caspase-dependent and caspase-independent cascades. It indicates that plumbagin can be potentially developed as a novel therapeutic agent against pancreatic cancer.

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    • "The plant metabolite, plumbagin (5-hydroxy-2 methyl-1,5-naphthoquinone), is a naphthoquinone derivative that was originally identified from the roots of plant Plumbago and belongs to one of the largest and diverse groups of plant metabolites [1], [2], [3]. Plumbagin has potent anti-proliferative and apoptotic activities in various types of human cancers, but the mechanisms underlying the anticancer activity are only partially understood. "
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    ABSTRACT: Drug-induced haploinsufficiency (DIH) in yeast has been considered a valuable tool for drug target identification. A plant metabolite, plumbagin, has potent anticancer activity via reactive oxygen species (ROS) generation. However, the detailed molecular targets of plumbagin for ROS generation are not understood. Here, using DIH and heterozygous deletion mutants of the fission yeast Schizosaccharomyces pombe, we identified 1, 4-phopshatidylinositol 5-kinase (PI5K) its3 as a new molecular target of plumbagin for ROS generation. Plumbagin showed potent anti-proliferative activity (GI(50); 10 ┬ÁM) and induced cell elongation and septum formation in wild-type S. pombe. Furthermore, plumbagin dramatically increased the intracellular ROS level, and pretreatment with the ROS scavenger, N-acetyl cysteine (NAC), protected against growth inhibition by plumbagin, suggesting that ROS play a crucial role in the anti-proliferative activity in S. pombe. Interestingly, significant DIH was observed in an its3-deleted heterozygous mutant, in which ROS generation by plumbagin was higher than that in wild-type cells, implying that its3 contributes to ROS generation by plumbagin in this yeast. In MCF7 human breast cancer cells, plumbagin significantly decreased the level of a human ortholog, 1, 4-phopshatidylinositol 5-kinase (PI5K)-1B, of yeast its3, and knockdown of PI5K-1B using siPI5K-1B increased the ROS level and decreased cell viability. Taken together, these results clearly show that PI5K-1B plays a crucial role in ROS generation as a new molecular target of plumbagin. Moreover, drug target screening using DIH in S. pombe deletion mutants is a valuable tool for identifying molecular targets of anticancer agents.
    Full-text · Article · Sep 2012 · PLoS ONE
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    • "In recent years, herbal medicines have been investigated extensively as potential alternative therapies for the treatment of various cancers (in both clinical and pre-clinical studies), including liver, lung, ovarian, breast, prostate, and pancreatic cancers as well as leukemia (Harinantenaina et al., 2010; Lucas et al., 2010; McCulloch et al., 2006; Motoo and Sawabu, 1994; Szliszka et al., 2011; Thoppil and Bishayee, 2011). Herbal treatments for pancreatic cancer, alone or in combination with conventional anticancer agents, have been examined with beneficial effects (Aghdassi et al., 2007; Chen et al., 2009; Patil et al., 2009; Sahu et al., 2009). There is a growing interest in exploring herbal medicines to overcome the resistance of pancreatic cancer to clinical treatments. "
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    ABSTRACT: Pancreatic cancer is difficult to detect early and responds poorly to chemotherapy. A breakthrough in the development of new therapeutic agents is urgently needed. Eriocalyxin B (EriB), isolated from the Isodon eriocalyx plant, is an ent-kaurane diterpenoid with promise as a broad-spectrum anti-cancer agent. The anti-leukemic activity of EriB, including the underlying mechanisms involved, has been particularly well documented. In this study, we demonstrated for the first time EriB's potent cytotoxicity against four pancreatic adenocarcinoma cell lines, namely PANC-1, SW1990, CAPAN-1, and CAPAN-2. The effects were comparable to that of the chemotherapeutic camptothecin (CAM), but with much lower toxicity against normal human liver WRL68 cells. EriB's cytoxicity against CAPAN-2 cells was found to involve caspase-dependent apoptosis and cell cycle arrest at the G2/M phase. Moreover, the p53 pathway was found to be activated by EriB in these cells. Furthermore, in vivo studies showed that EriB inhibited the growth of human pancreatic tumor xenografts in BALB/c nude mice without significant secondary adverse effects. These results suggest that EriB should be considered a candidate for pancreatic cancer treatment.
    Preview · Article · Apr 2012 · Toxicology and Applied Pharmacology
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    • "The aerial parts contain naphthoquinones, sitosterol, lupeol, lupenylacetate, hentriacontane, and amino acids. Plant contains naphthaquinones (Figure 2a), plumbagin (Figure 2b), chloroplumbagin, droserone, zeylinone (Figure 2c), isozeylinone, plumbagic acid, plumba-zeylanone, naphthelenone, isonaphthelenone, isoshinanolone (Anonymous, 1989; Chen et al., 2011; Kumar et al., 2009). Aspartic acid, tryptophan, tyrosine, threonine, alanine, histidine, glycine, methionine, hydroxyproline, were isolated from the aerial parts (Elizabeth, 2002). "
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    ABSTRACT: The present review aimed to compile up to date and comprehensive information of Plumbago zeylanica with special emphasis on its phytochemistry, various scientifically documented pharmacological activities, traditional and folk medicine uses. Traditional system of medicinal consists of large number of plants with various medicinal and pharmacological uses and hence represents a priceless tank of new bioactive molecules. P. zeylanica is one amongst these, found all over the world. In this review, we have attempted to highlight the work carried out on P. zeylanica. It is commonly known as 'Chitraka', and has been recognized in different traditional system of medicines for the treatment of various diseases of human beings in the form of paste and powder. Plant mainly contains naphthoquinones and steroidal compounds. Different parts of this plant are traditionally claimed to be used for the treatment of ailments including anti-fungal, anti-tumor, disease of heart, rheumatic pains, liver diseases, fever, diabetes, and kidney disease to list of few.
    Preview · Article · Dec 2011 · African journal of pharmacy and pharmacology
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