Plumbagin

Cancer Lett. 2015 Feb 1;357(1):265-78.

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

Maintaining cellular redox homeostasis is imperative for the survival and normal functioning of cells.
METHODS AND RESULTS:
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.
CONCLUSIONS:
In conclusion, oxidative stress mediated tumor cytotoxicity operates through sustained JNK activation via a novel redox-mediated regulation of MKP-1 and MKP-2.

Curr Drug Deliv. 2015 Mar 16.

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

Stable nano-formulation of Plumbagin nanoparticles from Plumbago zeylanica root extract was explored as a potential natural drug against prostate cancer.
METHODS AND RESULTS:
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.
CONCLUSIONS:
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.

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

Anti-fibrotic effect of plumbagin on CCl₄-lesioned rats.[Pubmed: 25824458]

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 AND RESULTS:
We used rat models to assess the potential benefits of Plumbagin against CCl₄-induced liver fibrosis. The results showed that Plumbagin lowered the serum concentrations of liver functional enzymes (ALT, AST, ALB, TBIL) in CCl₄-fibrotic rats while reducing inflammatory cytokine levels (IL-6, TNF-α). 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-κB and TLR-4 mRNA in CCl₄-lesioned livers. As revealed in the immunohistochemical assay, Plumbagin-administered rats showed reduced levels of α-SMA and TNF-α immunoreactive cells in liver tissue.
CONCLUSIONS:
Collectively, these findings offer appealing evidence that Plumbagin may serve as an anti-fibrotic medication through inactivating the NF-κB/TLR-4 pathway that is associated with inflammatory reactions, thereby mitigating liver fibrosis.

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

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

Long-term and high-dose glucocorticoids (GCs) supplementation has been linked to osteoporosis.
METHODS AND RESULTS:
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 μM. Further, 10 μM 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.
CONCLUSIONS:
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.

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

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

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.
METHODS AND RESULTS:
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.
CONCLUSIONS:
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.