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REVIEW 1

Anticancer compound plumbagin and its molecular targets: a structural insight into the inhibitory mechanisms using computational approaches.
AUTHOR : Jamal MS1, Parveen S2, Beg MA1, Suhail M1, Chaudhary AG1, Damanhouri GA1, Abuzenadah
AM , Rehan M .
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Abstract
Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) is a naphthoquinone derivative from the roots of plant Plumbago zeylanica and belongs to one of the largest and diverse groups of plant metabolites. The anticancer and antiproliferative activities of plumbagin have been observed in animal models as well as in cell cultures. Plumbagin exerts inhibitory effects on multiple cancer-signaling proteins, however, the binding mode and the molecular interactions have not yet been elucidated for most of these protein targets. The present study is the first attempt to provide structural insights into the binding mode of plumbagin to five cancer signaling proteins viz. PI3K, AKT1/PKB, Bcl-2, NF-B, and Stat3 using molecular docking and (un)binding simulation analysis. We validated plumbagin docking to these targets with previously known important residues. The study also identified and characterized various novel interacting residues of these targets which mediate the binding of plumbagin. Moreover, the exact modes of inhibition when multiple mode of inhibition existed was also shown. Results indicated that the engaging of these important interacting residues in plumbagin binding leads to inhibition of these cancer-signaling proteins which are key players in the pathogenesis of cancer and thereby ceases the progression of the disease.

REVIEW 2
Plumbagin attenuates cancer cell growth and osteoclast formation in the bone microenvironment of mice
AUTHOR :
Yan W , Wang TY , Fan QM , Du L , Xu JK , Zhai ZJ , Li HW , Tang TT .
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Abstract
AIM: To investigate the effects of plumbagin, a naphthoquinone derived from the medicinal plant Plumbago zeylanica, on human breast cancer cell growth and the cancer cell-induced osteolysis in the bone microenvironment of mice. Human breast cancer cell subline MDA-MB-231SA with the ability to spread and grow in the bone was tested. The cell proliferation was determined using the CCK-8 assay. Apoptosis was detected with Annexin V/PI double-labeled flow cytometry. Red fluorescent protein-labeled MDA-MB-231SArfp cells

were injected into the right tibia of female BALB/c-nu/nu mice. Three days after the inoculation, the mice were injected with plumbagin (2, 4, or 6 mg/kg, ip) 5 times per week for 7 weeks. The growth of the tumor cells was monitored using an in vivo imaging system. After the mice were sacrificed, the hind limbs were removed for radiographic and histological analyses. RESULTS: Plumbagin (2.5-20 mol/L) concentration-dependently inhibited the cell viability and induced apoptosis of MDA-MB-231SA cells in vitro (the IC50 value of inhibition of c ell viability was 14.7 mol/L). Administration of plumbagin to breast cancer bearing mice delayed the tumor growth by 2-3 weeks and reduced the tumor volume by 44%-74%. The in vivo imaging study showed that plumbagin dose-dependently inhibited MDA-MB-231SArfp cell growth in bone microenvironment. Furthermore, X-ray images and micro-CT study demonstrated that plumbagin reduced bone erosion area and prevented a decrease in bone tissue volume. Histological studies showed that plumbagin dose-dependently inhibited the breast cancer cell growth, enhanced the cell apoptosis and reduced the number of TRAcP-positive osteoclasts. CONCLUSION: Plumbagin inhibits the cell growth and induces apoptosis in human breast cancer cells in mice bone microenvironment, leading to significant reduction in osteolytic lesions caused by the tumor cells.

REVIEW 3
Polyketide synthesis in tobacco plants transformed with a Plumbago zeylanica type III hexaketide synthase.
AUTHOR :
Jadhav S , Phapale P , Thulasiram HV , Bhargava S .
1 2 3 4

Abstract
A type III polyketide synthase from Plumbago zeylanica (PzPKS) was cloned and expressed in tobacco plants to study whether the transgenic tobacco plants expressing PzPKS synthesize the pharmacologically important polyketide, plumbagin. High resolution mass spectrometry based metabolite profiling of two transgenic events and wild type tobacco plants was carried out to investigate changes in polyketides, including plumbagin. Ten polyketides, which included six pyrones and four naphthalene derivatives, were identified in PzPKS transgenic plants. While one pyrone, styryl-2-pyranone, was detected in both, wild type and transgenic tobacco plants, three pyrones were expressed only in the leaves of transgenic tobacco plants. The transgenic tobacco plants did not accumulate plumbagin, but showed accumulation of isoshinanolone in the roots, which is postulated to be the reduction product of plumbagin. In addition, leaves of transgenic tobacco plants accumulated 3-methyl-1,8-naphthalenediol, a postulated precursor of plumbagin. The results indicated the requirement of additional Plumbago-specific components in the biosynthetic pathway of this polyketide.

REVIEW 4
Plumbagin induces the apoptosis of human tongue carcinoma cells through the mitochondria-mediated pathway
AUTHOR :
Qiu JX , He YQ, Wang Y, Xu RL, Qin Y, Shen X, Zhou SF, Mao ZF.
1

Abstract
BACKGROUND: Plumbagin, a quinonoid constituent isolated from the root of Plumbago zeylanica L., has been proven to possess anti-tumor activity both in vitro and in vivo. However, its anti-tumor properties for human tongue carcinoma have not been reported. This study aimed to investigate the inhibitory effect and the underlying mechanism of plumbagin on the growth of human tongue carcinoma cells. MATERIAL AND METHODS: Cell proliferation ability was detected by EdU incorporation assay and colony formation assay. Cell-cycle distribution was determined by flow cytometric analysis using propidium iodide (PI) staining. Cellular apoptosis was then evaluated by flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Western blotting was applied to assay the expression of Bax and Bcl-2. RESULTS: Plumbagin inhibited the growth and proliferation of Tca8113 cells in vitro in a concentration- and timedependent manner. The cell cycles of plumbagin-treated Tca8113 cells were arrested at the G2/M phase. Cells treated with plumbagin presented the characteristic morphological changes of apoptosis. The ratio of Bax/Bcl-2 was raised by plumbagin in a concentration-dependent manner. CONCLUSIONS: These results indicate that plumbagin induces the apoptosis of Tca8113 cells through mitochondriamediated pathway.

REVIEW 5
Plumbagin from Plumbago Zeylanica L induces apoptosis in human non-small cell lung cancer cell lines through NF- B inactivation.
AUTHOR :
Xu TP , Shen H, Liu LX, Shu YQ.
1

Abstract
OBJECTIVE: To detect effects of plumbagin on proliferation and apoptosis in non-small cell lung cancer cell lines, and investigate the underlying mechanisms.

MATERIALS AND METHODS: Human non-small cell lung cancer cell lines A549, H292 and H460 were treated with various concentrations of plumbagin. Cell proliferation rates was determined using both cell counting kit-8 (CCK8) and clonogenic assays. Apoptosis was detected by annexin V/propidium iodide double-labeled flow cytometry and TUNEL assay. The levels of reactive oxygen species (ROS) were detected by flow cytometry. Activity of NF-B was examined by electrophoretic mobility shift assay (EMSA) and luciferase reporter assay. Western blotting was used to assess the expression of both NF-B regulated apoptoticrelated gene and activation of p65 and IB. RESULTS: Plumbagin dose-dependently inhibited proliferation of the lung cancer cells. The IC50 values of plumbagin in A549, H292, and H460 cells were 10.3 mol/L, 7.3 mol/L, and 6.1 mol/L for 12 hours, respectively. The compound concentration-dependently induced apoptosis of the three cell lines. Treatment with plumbagin increased the intracellular level of ROS, and inhibited the activation of NK-B. In addition to inhibition of NF-B/p65 nuclear translocation, the compound also suppressed the degradation of IB. ROS scavenger NAC highly reversed the effect of plumbagin on apoptosis and inactivation of NK-B in H460 cell line. Treatment with plumbagin also increased the activity of caspase-9 and caspase-3, downregulated the expression of Bcl-2, upregulated the expression of Bax, Bak, and CytC. CONCLUSIONS: Plumbagin inhibits cell growth and induces apoptosis in human lung cancer cells through an NF-Bregulated mitochondrial-mediated pathway, involving activation of ROS.

REVIEW 6
Plumbagin, a medicinal plant (Plumbago zeylanica)-derived 1,4naphthoquinone, inhibits growth and metastasis of human prostate cancer PC-3M-luciferase cells in an orthotopic xenograft mouse model.

AUTHOR :
K, Verma AK.

Hafeez BB , Zhong W, Fischer JW, Mustafa A, Shi X, Meske L, Hong H, Cai W, Havighurst T, Kim

Abstract
We present here first time that Plumbagin (PL), a medicinal plant-derived 1,4-naphthoquinone, inhibits the growth and metastasis of human prostate cancer (PCa) cells in an orthotopic xenograft mouse model. In this study, human PCa PC-3M-luciferase cells (2 10(6)) were injected into the prostate of athymic nude mice. Three days post cell implantation, mice were treated with PL (2 mg/kg body wt. i.p. five days in a week) for 8 weeks. Growth and metastasis of PC-3M-luciferase cells was examined weekly by bioluminescence imaging of live mice. PL-treatment significantly (p = 0.0008) inhibited the growth of orthotopic xenograft tumors. Results demonstrated a significant inhibition of metastasis into liver (p = 0.037), but inhibition of metastasis into the lungs (p = 0.60) and lymph nodes (p = 0.27) was not observed

to be significant. These results were further confirmed by histopathology of these organs. Results of histopathology demonstrated a significant inhibition of metastasis into lymph nodes (p = 0.034) and lungs (p = 0.028), and a trend to significance in liver (p = 0.075). None of the mice in the PL-treatment group showed PCa metastasis into the liver, but these mice had small metastasis foci into the lymph nodes and lungs. However, control mice had large metastatic foci into the lymph nodes, lungs, and liver. PL-caused inhibition of the growth and metastasis of PC-3M cells accompanies inhibition of the expression of: 1) PKC, pStat3Tyr705, and pStat3Ser727, 2) Stat3 downstream target genes (survivin and Bcl(xL)), 3) proliferative markers Ki-67 and PCNA, 4) metastatic marker MMP9, MMP2, and uPA, and 5) angiogenesis markers CD31 and VEGF. Taken together, these results suggest that PL inhibits tumor growth and metastasis of human PCa PC3-M-luciferase cells, which could be used as a therapeutic agent for the prevention and treatment of human PCa.

REVIEW 7
Plumbagin inhibits prostate cancer development in TRAMP mice via targeting PKC, Stat3 and neuroendocrine markers.

AUTHOR :

Hafeez BB , Zhong W, Mustafa A, Fischer JW, Witkowsky O, Verma AK.

Abstract
Plumbagin (PL), 5-hydroxy-2-methyl-1,4-naphthoquinone, is a quinoid constituent isolated from the roots of the medicinal plant Plumbago zeylanica L. (also known as chitrak). PL has also been found in Juglans regia (English Walnut), Juglans cinerea (whitenut) and Juglans nigra (blacknut). The roots of P. zeylanica have been used in Indian and Chinese systems of medicine for more than 2500 years for the treatment of various types of ailments. We were the first to report that PL inhibits the growth and invasion of hormone refractory prostate cancer (PCa) cells [Aziz,M.H. et al. (2008) Plumbagin, a medicinal plantderived naphthoquinone, is a novel inhibitor of the growth and invasion of hormone-refractory prostate cancer. Cancer Res., 68, 9024-9032.]. Now, we present that PL inhibits in vivo PCa development in the transgenic adenocarcinoma of mouse prostate (TRAMP). PL treatment (2 mg/kg body weight i.p. in 0.2 ml phosphate-buffered saline, 5 days a week) to FVB-TRAMP resulted in a significant (P < 0.01) decrease in prostate tumor size and urogenital apparatus weights at 13 and 20 weeks. Histopathological analysis revealed that PL treatment inhibited progression of prostatic intraepithelial neoplasia (PIN) to poorly differentiated carcinoma (PDC). No animal exhibited diffuse tumor formation in PL-treated group at 13 weeks, whereas 75% of the vehicle-treated mice elicited diffuse PIN and large PDC at this stage. At 20 weeks, 25% of the PL-treated animals demonstrated diffuse PIN and 75% developed small PDC, whereas 100% of the vehicle-treated mice showed large PDC. PL treatment inhibited expression of protein kinase C epsilon (PKC), signal transducers and activators of transcription 3 phosphorylation, proliferating cell nuclear antigen and neuroendocrine markers (synaptophysin and chromogranin-A) in excised prostate tumor tissues. Taken together, these results further suggest PL could be a novel chemopreventive agent against PCa.

REVIEW 8 http://www.ncbi.nlm.nih.gov/pubmed/?term=Plumbago+zeyl anica

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