Plumbagin

The herbs of Plumbago zeylanica L.

IC50: 11.69 μM for A549 cells

Plumbagin, a quinonoid constituent isolated from the root of Plumbago zeylanica L., has been shown to exert anticarcinogenic, antiatherosclerotic, and antimicrobial effects.

In vitro: Plumbagin exhibited effective cell growth inhibition via inducing cancer cells to undergo G2/M phase arrest and apoptosis. Blockade of cell cycle was associated with increased levels of p21 and reduced amounts of Cdc2, Cdc25C and cyclinB1. Plumbagin treatment also found to enhance the levels of inactivated phosphorylated Cdc2 and Cdc25C. Blockade of p53 activity partially decreased plumbagin-induced apoptosis and G2/M arrest, indicating it might be operated by p53-dependent and independent pathway [1].

In vivo: To determine whether plumbagin inhibited the in vivo tumor growth, A549 cells were injected into nude mice. Tumor growth inhibition was most evident in mice treated with plumbagin at 2 mg/kg/day, where around 80% reductions in tumor size were observed, in contrast with mice treated with the vehicle. No sign of toxicity was observed in plumbagin-treated mice as judged by monitoring body weight [1].

Clinical trial: N/A

Reference:
[1] Hsu YL,Cho CY,Kuo PL,Huang YT,Lin CC.  Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) induces apoptosis and cell cycle arrest in A549 cells through p53 accumulation via c-Jun NH2-terminal kinase-mediated phosphorylation at serine 15 in vitro and in vivo. J Pharmacol Exp Ther.2006 Aug;318(2):484-94.

Plumbagin induces growth inhibition of human glioma cells by downregulating the expression and activity of FOXM1.[Pubmed:25528634]

J Neurooncol. 2015 Feb;121(3):469-77.

Plumbagin, a natural quinonoid constituent isolated from the root of medicinal plant Plumbago zeylanica L, has exhibited anti-tumor and anti-proliferative activities in various tumor cell lines as well as in animal tumor models. However, its anticancer effects and the mechanisms underlying its suppression of glioma cell growth have not been elucidated. Oncogenic transcription factor Forkhead Box M1 (FOXM1) has garnered particular interest in recent years as a potential target for the prevention and/or therapeutic intervention in glioma, nevertheless, less information is currently available regarding FOXM1 inhibitor. Here, we reported that Plumbagin could effectively inhibit cell proliferation, migration and invasion and induce apoptosis of glioma cells. Cell cycle assay showed that Plumbagin induced G2/M arrest. Interestingly, we found that Plumbagin decreased the expression of FOXM1 both at mRNA level and protein level. Plumbagin also inhibited the transactivation ability of FOXM1, resulting in down-regulating the expression of FOXM1 downstream target genes, such as cyclin D1, Cdc25B, survivin, and increasing the expression of p21(CIP1) and p27(KIP1). Most importantly, down-regulation of FOXM1 by siFOXM1 transfection enhanced Plumbagin-induced change in viability. On the contrary, over-expression of FOXM1 by cDNA transfection reduced Plumbagin-induced glioma cell growth inhibition. These results suggest that Plumbagin exhibits its anticancer activity partially by inactivation of FOXM1 signaling pathway in glioma cells. Our findings indicate that Plumbagin may be considered as a potential natural FOXM1 inhibitor, which could contribute to the development of new anticancer agent for therapy of gliomas.

Plumbagin induces apoptosis in lymphoma cells via oxidative stress mediated glutathionylation and inhibition of mitogen-activated protein kinase phosphatases (MKP1/2).[Pubmed:25444924]

Cancer Lett. 2015 Feb 1;357(1):265-278.

Maintaining cellular redox homeostasis is imperative for the survival and normal functioning of cells. This study describes the role and regulation of MAPKinases in oxidative stress mediated apoptosis. Plumbagin, a vitamin K3 analog and a pro-oxidant, was employed and it induced apoptosis in both mouse and human T-cell lymphoma cell lines via increased oxidative stress, caspase activity and loss of mitochondrial membrane potential. The pro-oxidant and cytotoxic effects of Plumbagin were sensitive to antioxidants indicating a decisive role of cellular redox balance. Plumbagin induced persistent activation of JNK and pharmacological inhibition as well as shRNA-mediated JNK knock-down rescued cells from Plumbagin-induced apoptosis. Further, Plumbagin induced cytochrome c release, FasL expression and Bax levels via activation of JNK pathway. Exposure of lymphoma cells to Plumbagin led to inhibition of total and specific phosphatase activity, increased total protein S-glutathionylation and induced glutathionylation of dual specific phosphatase- 1 and 4 (MKP-1 and MKP-2). The in vivo anti-tumor efficacy of Plumbagin was demonstrated using a mouse model. In conclusion, oxidative stress mediated tumor cytotoxicity operates through sustained JNK activation via a novel redox-mediated regulation of MKP-1 and MKP-2.

Anti-fibrotic effect of plumbagin on CCl(4)-lesioned rats.[Pubmed:25824458]

Cell Physiol Biochem. 2015;35(4):1599-608.

BACKGROUND/AIMS: Our previous studies have shown that Plumbagin effectively inhibits hepatic stellate cell (HSC) proliferation. Thus, Plumbagin-mediated anti-fibrotic effects in vivo merit further investigation. METHODS: We used rat models to assess the potential benefits of Plumbagin against CCl(4)-induced liver fibrosis. RESULTS: The results showed that Plumbagin lowered the serum concentrations of liver functional enzymes (ALT, AST, ALB, TBIL) in CCl(4)-fibrotic rats while reducing inflammatory cytokine levels (IL-6, TNF-alpha). As reflected in pathological examinations, rats that were administered Plumbagin showed decreased collagen markers (HA, LN, PCIII and CIV) in liver tissues and improved hepatocellular impairments. In addition, Plumbagin contributed to down-regulating NF-kappaB and TLR-4 mRNA in CCl(4)-lesioned livers. As revealed in the immunohistochemical assay, Plumbagin-administered rats showed reduced levels of alpha-SMA and TNF-alpha immunoreactive cells in liver tissue. CONCLUSION: Collectively, these findings offer appealing evidence that Plumbagin may serve as an anti-fibrotic medication through inactivating the NF-kappaB/TLR-4 pathway that is associated with inflammatory reactions, thereby mitigating liver fibrosis.

Plumbagin protects against glucocorticoid-induced osteoporosis through Nrf-2 pathway.[Pubmed:25939783]

Cell Stress Chaperones. 2015 Jul;20(4):621-9.

Long-term and high-dose glucocorticoids (GCs) supplementation has been linked to osteoporosis. In this study, we studied the protective role of Plumbagin against GC-induced cell damage in MC3T3-E1 cells. The effect of dexamethasone (DEX) and Plumbagin on cell viability was determined. DEX showed as IC-50 value of 95 muM. Further, 10 muM Plumbagin treatment effectively ameliorated DEX-induced cell death by increasing the cell viability to 92 %. A further effect of Plumbagin on DEX-induced oxidative stress was determined through reactive oxygen species (ROS) level, lipid peroxide content, and antioxidant status. Nrf-2 nuclear localization was analyzed through immunofluorescence. Protein expression of redox regulator Nrf-2 and their target genes HO-1 and NQO1 and osteogenic markers (OCN, OPN Runx-2) were determined by Western blot. Apoptotic effect was analyzed by mitochondrial membrane potential and caspase activities (3, 8, and 9). The results showed that DEX treatment showed a significant increase in oxidative stress through increased ROS levels and downregulation of cytoprotective antioxidant proteins and antioxidant enzyme activities. Further DEX treatment downregulated the osteogenic markers and upregulated apoptosis through decreased mitochondrial membrane potential and upregulation of caspase activities. Plumbagin treatment significantly reversed the levels of oxidative stress and apoptotic markers and protected against DEX-induced cell damage. Further, Plumbagin treatment significantly improved the expression of osteogenic markers compared to DEX treatment. In conclusion, the present study shows that Plumbagin offers significant protective role against DEX-induced cellular damage via regulating oxidative stress, apoptosis, and osteogenic markers.

Plumbagin Nanoparticles Induce Dose and pH Dependent Toxicity on Prostate Cancer Cells.[Pubmed:25772029]

Curr Drug Deliv. 2015;12(6):709-16.

Stable nano-formulation of Plumbagin nanoparticles from Plumbago zeylanica root extract was explored as a potential natural drug against prostate cancer. Size and morphology analysis by DLS, SEM and AFM revealed the average size of nanoparticles prepared was 100+/-50nm. In vitro cytotoxicity showed concentration and time dependent toxicity on prostate cancer cells. However, Plumbagin crude extract found to be highly toxic to normal cells when compared to Plumbagin nanoformulation, thus confirming nano Plumbagin cytocompatibility with normal cells and dose dependent toxicity to prostate cells. In vitro hemolysis assay confirmed the blood biocompatibility of the Plumbagin nanoparticles. In wound healing assay, Plumbagin nanoparticles provided clues that it might play an important role in the anti-migration of prostate cancer cells. DNA fragmentation revealed that partial apoptosis induction by Plumbagin nanoparticles could be expected as a potent anti-cancer effect towards prostate cancer.

The natural anticancer agent plumbagin induces potent cytotoxicity in MCF-7 human breast cancer cells by inhibiting a PI-5 kinase for ROS generation.[Pubmed:23028742]

PLoS One. 2012;7(9):e45023.

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 microM) 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.

Inhibition of lysine acetyltransferase KAT3B/p300 activity by a naturally occurring hydroxynaphthoquinone, plumbagin.[Pubmed:19570987]

J Biol Chem. 2009 Sep 4;284(36):24453-64.

Lysine acetyltransferases (KATs), p300 (KAT3B), and its close homologue CREB-binding protein (KAT3A) are probably the most widely studied KATs with well documented roles in various cellular processes. Hence, the dysfunction of p300 may result in the dysregulation of gene expression leading to the manifestation of many disorders. The acetyltransferase activity of p300/CREB-binding protein is therefore considered as a target for new generation therapeutics. We describe here a natural compound, Plumbagin (RTK1), isolated from Plumbago rosea root extract, that inhibits histone acetyltransferase activity potently in vivo. Interestingly, RTK1 specifically inhibits the p300-mediated acetylation of p53 but not the acetylation by another acetyltransferase, p300/CREB-binding protein -associated factor, PCAF, in vivo. RTK1 inhibits p300 histone acetyltransferase activity in a noncompetitive manner. Docking studies and site-directed mutagenesis of the p300 histone acetyltransferase domain suggest that a single hydroxyl group of RTK1 makes a hydrogen bond with the lysine 1358 residue of this domain. In agreement with this, we found that indeed the hydroxyl group-substituted Plumbagin derivatives lost the acetyltransferase inhibitory activity. This study describes for the first time the chemical entity (hydroxyl group) required for the inhibition of acetyltransferase activity.

Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) induces apoptosis and cell cycle arrest in A549 cells through p53 accumulation via c-Jun NH2-terminal kinase-mediated phosphorylation at serine 15 in vitro and in vivo.[Pubmed:16632641]

J Pharmacol Exp Ther. 2006 Aug;318(2):484-94.

This study first investigates the anticancer effect of Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) in human nonsmall cell lung cancer cells, A549. Plumbagin has exhibited effective cell growth inhibition by inducing cancer cells to undergo G2/M phase arrest and apoptosis. Blockade of cell cycle was associated with increased levels of p21 and reduced amounts of cyclinB1, Cdc2, and Cdc25C. Plumbagin treatment also enhanced the levels of inactivated phosphorylated Cdc2 and Cdc25C. Blockade of p53 activity by dominant-negative p53 transfection partially decreased Plumbagin-induced apoptosis and G2/M arrest, suggesting it might be operated by p53-dependent and independent pathway. Plumbagin treatment triggered the mitochondrial apoptotic pathway indicated by a change in Bax/Bcl-2 ratios, resulting in mitochondrial membrane potential loss, cytochrome c release, and caspase-9 activation. We also found that c-Jun NH2-terminal kinase (JNK) is a critical mediator in Plumbagin-induced cell growth inhibition. Activation of JNK by Plumbagin phosphorylated p53 at serine 15, resulting in increased stability of p53 by decreasing p53 and MDM2 interaction. SP600125 (anthra [1,9-cd]pyrazol-6(2H)-one-1,9-pyrazoloanthrone), a specific inhibitor of JNK, significantly decreased apoptosis by inhibiting the phosphorylation of p53 (serine 15) and subsequently increased the interaction of p53 and MDM2. SP6000125 also inhibited the phosphorylation of Bcl-2 (Ser70) induced by Plumbagin. Further investigation revealed that Plumbagin's inhibition of cell growth effect was also evident in a nude mice model. Taken together, these results suggest a critical role for JNK and p53 in Plumbagin-induced G2/M arrest and apoptosis of human nonsmall cell lung cancer cells.

Plumbagin induces G2-M arrest and autophagy by inhibiting the AKT/mammalian target of rapamycin pathway in breast cancer cells.[Pubmed:17172425]

Mol Cancer Ther. 2006 Dec;5(12):3209-21.

This study is the first to investigate the anticancer effect of Plumbagin in human breast cancer cells. Plumbagin exhibited cell proliferation inhibition by inducing cells to undergo G2-M arrest and autophagic cell death. Blockade of the cell cycle was associated with increased p21/WAF1 expression and Chk2 activation, and reduced amounts of cyclin B1, cyclin A, Cdc2, and Cdc25C. Plumbagin also reduced Cdc2 function by increasing the association of p21/WAF1/Cdc2 complex and the levels of inactivated phospho-Cdc2 and phospho-Cdc25C by Chk2 activation. Plumbagin triggered autophagic cell death but not predominantly apoptosis. Pretreatment of cells with autophagy inhibitor bafilomycin suppressed Plumbagin-mediated cell death. We also found that Plumbagin inhibited survival signaling through the phosphatidylinositol 3-kinase/AKT signaling pathway by blocking the activation of AKT and downstream targets, including the mammalian target of rapamycin, forkhead transcription factors, and glycogen synthase kinase 3beta. Phosphorylation of both of mammalian target of rapamycin downstream targets, p70 ribosomal protein S6 kinase and 4E-BP1, was also diminished. Overexpression of AKT by AKT cDNA transfection decreased Plumbagin-mediated autophagic cell death, whereas reduction of AKT expression by small interfering RNA potentiated the effect of Plumbagin, supporting the inhibition of AKT being beneficial to autophagy. Furthermore, suppression of AKT by Plumbagin enhanced the activation of Chk2, resulting in increased inactive phosphorylation of Cdc25C and Cdc2. Further investigation revealed that Plumbagin inhibition of cell growth was also evident in a nude mouse model. Taken together, these results imply a critical role for AKT inhibition in Plumbagin-induced G2-M arrest and autophagy of human breast cancer cells.

Plumbagin (2-Methyljuglone) is a naphthoquinone isolated from Plumbago zeylanica L, exhibits anticancer and antiproliferative activities.

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