Disease relevance of Plumbagin

• Mu dX phage was used to isolate three gene fusions to the lacZ gene (soi::lacZ; soi for superoxide radical inducible) that were induced by treatment with superoxide radical anion generators such as paraquat and plumbagin [1].
• Increasing the intracellular flux of O-2 by incubating aerobic Escherichia coli with paraquat or plumbagin markedly lowered the alpha, beta-dihydroxyisovalerate dehydratase activity detectable in extracts from these cells [2].
• Plumbagin increased oxygen consumption by S. sanguis and imposed an oxygen-dependent toxicity [3].
• When Mycobacterium smegmatis carrying the M. bovis katG gene was treated with nontoxic levels of plumbagin, a generator of superoxide, the bacteriostatic activity of INH increased unless a plasmid-borne superoxide dismutase gene was also present [4].
• Cells pretreated with plumbagin could partially reactivate lambda phage damaged by exposure to riboflavin plus light, a treatment that produces active oxygen species [5].

High impact information on Plumbagin

• Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) suppresses NF-kappaB activation and NF-kappaB-regulated gene products through modulation of p65 and IkappaBalpha kinase activation, leading to potentiation of apoptosis induced by cytokine and chemotherapeutic agents [6].
• Plumbagin, derived from the medicinal plant Plumbago zeylanica, modulates cellular proliferation, carcinogenesis, and radioresistance, all known to be regulated by the activation of the transcription factor NF-kappaB, suggesting plumbagin might affect the NF-kappaB activation pathway [6].
• However, plumbagin did not inhibit p65 binding to DNA when cells were transfected with the p65 plasmid containing cysteine 38 mutated to serine [6].
• These findings suggest that plumbagin induced p21 levels play a regulatory role in cell cycle arrest, apoptosis, and polbeta-dependent and -independent LP-BER pathways in MEF cells [7].
• Long-patch base excision repair of apurinic/apyrimidinic site DNA is decreased in mouse embryonic fibroblast cell lines treated with plumbagin: involvement of cyclin-dependent kinase inhibitor p21Waf-1/Cip-1 [7].

Chemical compound and disease context of Plumbagin

• Furthermore, mild pressure treatment strongly sensitized E. coli toward t-butylhydroperoxide and the superoxide generator plumbagin [8].
• Actively growing Escherichia coli cells exposed to plumbagin, a redox cycling quinone that increases the flux of O2- radicals in the cell, were mutagenized or killed by this treatment [5].
• Further analysis determined that the mutant strain was not only sensitive with regard to survival under heat stress, but was also markedly susceptible to thiol-specific oxidant diamide and redox cycling compounds, including menadione and plumbagin [9].
• Chemical modification of the lactose carrier of Escherichia coli by plumbagin, phenylarsinoxide or diethylpyrocarbonate affects the binding of galactoside [10].

Biological context of Plumbagin

• Plumbagin has exhibited effective cell growth inhibition by inducing cancer cells to undergo G2/M phase arrest and apoptosis [11].
• The cytotoxic effect of plumbagin induced cell death is through the generation of reactive oxygen species (ROS) and subsequent induction of apoptosis as demonstrated by the present data [12].
• SP6000125 also inhibited the phosphorylation of Bcl-2 (Ser70) induced by plumbagin [11].
• After 30 min of incubation with cardiac sarcoplasmic reticulum membrane vesicles, plumbagin inhibited Ca2+ uptake by the pump in a concentration-dependent manner (IC50 = 3 microM) [13].
• 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 [11].

Anatomical context of Plumbagin

• In the present investigation, we treated isogenic mouse embryonic fibroblast (MEF) cell lines containing wild-type (MEF-polbeta) or DNA polymerase beta (polbeta) gene-knockout (MEFpolbetaKO) with oxidative DNA-damaging agent, plumbagin, and examined its effect on p21 levels and BER activity [7].
• Of the enzymes and transport systems involved in the control of the cardiac contractility, the sarcoplasmic reticulum Ca2+ pump seemed to be a specific target for plumbagin [13].
• Cytotoxic action of juglone and plumbagin: a mechanistic study using HaCaT keratinocytes [14].
• Plumbagin decreased the binding between thrombin-stimulated platelets and neutrophils with an IC 50 of 62.9 microM [15].
• Plumbagin was also seen to exert a similar response on oxygen radical release by macrophages in vivo showing a clear correlation between oxygen radical release and the bactericidal activity [16].

Associations of Plumbagin with other chemical compounds

• Plumbagin also suppressed the direct binding of nuclear p65 and recombinant p65 to the DNA, and this binding was reversed by dithiothreitol both in vitro and in vivo [6].
• Similarly, plasmid DNA, within the endonuclease-deficient cells, exhibited more strand scissions and endonuclease III-sensitive sites upon aerobic exposure to plumbagin than did endonuclease-sufficient cells, and a low molecular weight scavenger of O2- was protective [17].
• The role of SOD for coping with the damaging effects of superoxide became evident after the increase in intracellular O2-. flux by growing cells under hyperoxygenation, but particularly by using redox cycling compounds such as plumbagin, paraquat and menadione [18].
• However, apoptosis induction was greater in BRCA1-blocked cells, the efficacy being in the order of plumbagin > tamoxifen > emodin [19].
• However, plumbagin stoichiometrically converted GSH to GSSG, indicating that redox cycling is its main metabolic pathway [14].

Gene context of Plumbagin

• 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 [11].
• This throws light on the fact that plumbagin may have chemotherapeutic potential as an anticancer agent in BRCA1-mutated ovarian cancer patients [19].
• Furthermore, suppression of AKT by plumbagin enhanced the activation of Chk2, resulting in increased inactive phosphorylation of Cdc25C and Cdc2 [20].
• This hypersensitive phenotype was specific to the lactoperoxidase system, since neither the sensitivity to hydrogen peroxide nor to the superoxide generator plumbagin was affected in the corA mutant [21].
• Cells pretreated with nonlethal doses of plumbagin showed enhanced survival upon exposure to high concentrations of plumbagin, but were unchanged in their susceptibility to far-UV irradiation. polA and recA mutants were not significantly more sensitive than wild type to killing by plumbagin [5].

Analytical, diagnostic and therapeutic context of Plumbagin

• These results present a reliable liquid chromatography coupled with tandem mass spectrometric (LC-MS/MS) method for the determination of plumbagin form herbal medicines [22].
• We also observed that plumbagin has strong anti-H. pylori activity, with 0.02-0.16 mg/ml as minimum inhibitory concentrations and 0.16-1.28 mg/ml as minimum bactericidal concentrations [23].
• Immobilization in calcium alginate enhanced the production of plumbagin by three, two and one folds compared to that of control, un-crosslinked alginate and CaCl(2) treated cells respectively [24].
• To examine the mechanisms of action in detail, antioxidant and pulse radiolysis studies with plumbagin were conducted [25].
• Reversed-phase HPLC indicated a relatively pure plumbagin extract with supercritical carbon dioxide [26].

References