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

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) PKCε, 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.

SUBMITTER: Hafeez BB

PROVIDER: S-EPMC3625495 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Chagas disease (CD) caused by the protozoan Trypanosoma cruzi affects more than six million people worldwide. Treatment is restricted to benznidazole (Bz) and nifurtimox (Nf) that display low activity in the later chronic stage besides triggering toxic events that result in treatment abandonment. Therefore, new therapeutic options are necessary. In this scenario, natural products emerge as promising alternatives to treat CD. In the family Plumbaginaceae, Plumbago sp. exhibits a broad spectrum of biological and pharmacological activities. Thus, our main objective was to evaluate, in vitro and in silico, the biological effect of crude extracts of root and of aerial parts of P. auriculata, as well as its naphthoquinone Plumbagin (Pb) against T. cruzi. The phenotypic assays revealed potent activity of the root extract against different forms (trypomastigote and intracellular forms) and strains (Y and Tulahuen), with a compound concentration that reduced 50% of the number of the parasite (EC50) values ranging from 1.9 to 3.9 µg/mL. In silico analysis showed that Pb is predicted to have good oral absorption and permeability in Caco2 cells, besides excellent probability of absorption by human intestinal cells, without toxic or mutagenic potential effects, not being predicted as a substrate or inhibitor of P-glycoprotein. Pb was as potent as Bz against intracellular forms and displayed a superior trypanosomicidal effect (about 10-fold) in bloodstream forms (EC50 = 0.8 µM) as compared to the reference drug (8.5 µM). The cellular targets of Pb on T. cruzi were evaluated using electron microscopy assays and the findings on bloodstream trypomastigotes showed several cellular insults related to the autophagic process. Regarding toxicity in mammalian cells, the root extracts and the naphthoquinone present a moderate toxic profile on fibroblasts and cardiac cell lines. Then, aiming to reduce host toxicity, the root extract and Pb were tested in combination with Bz, and the data showed additive profiles with the sum of the fractional inhibitory concentration indexes (ΣFICIs) being 1.45 and 0.87, respectively. Thus, our work reveals the promising antiparasitic activity of Plumbago auriculata crude extracts and its purified naphthoquinone Plumbagin against different forms and strains of Trypanosoma cruzi in vitro.

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

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