title: Luteolin, ellagic acid and punicic acid are natural products that inhibit prostate cancer metastasis.
abstract: Prostate cancer (PCa) is the second cause of cancer deaths in men in the USA. When the cancer recurs, early stages can be controlled with hormone ablation therapy to delay the rate of cancer progression but, over time, the cancer overcomes its hormone dependence, becomes highly aggressive and metastasizes. Clinical trials have shown that pomegranate juice (PJ) inhibits PCa progression. We have previously shown that the PJ components luteolin (L), ellagic acid (E) and punicic acid (P) together inhibit growth of hormone-dependent and -independent PCa cells and inhibit their migration and chemotaxis towards CXCL12, a chemokine that is important in PCa metastasis. On the basis of these findings, we hypothesized that L+E+P inhibit PCa metastasis in vivo. To test this possibility, we used a severe combined immunodeficiency mouse model in which luciferase-expressing human PCa cells were injected subcutaneously near the prostate. Tumor progression was monitored with bioluminescence imaging weekly. We found that L+E+P inhibits PC-3M-luc primary tumor growth, inhibits the CXCL12/CXCR4 axis for metastasis and none of the tumors metastasized. In addition, L+E+P significantly inhibits growth and metastasis of highly invasive Pten (-/-) ;K-ras (G12D) prostate tumors. Furthermore, L+E+P inhibits angiogenesis in vivo, prevents human endothelial cell (EC) tube formation in culture and disrupts preformed EC tubes, indicating inhibition of EC adhesion to each other. L+E+P also inhibits the angiogenic factors interleukin-8 and vascular endothelial growth factor as well as their induced signaling pathways in ECs. In conclusion, these results show that L+E+P inhibits PCa progression and metastasis.
authors.affiliation: Department of Cell biology and Neuroscience, University of California, Riverside, Riverside, CA 92521, USA, Department of Biomedical Engineering, School of Medicine, Shenzhen University, Guangdong 518060, China, Department of Molecular and Medical Pharmacology and Institute for Molecular Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA and Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Cell biology and Neuroscience, University of California, Riverside, Riverside, CA 92521, USA, Department of Biomedical Engineering, School of Medicine, Shenzhen University, Guangdong 518060, China, Department of Molecular and Medical Pharmacology and Institute for Molecular Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA and Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Wenfang
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Biomedical Engineering, School of Medicine, Shenzhen University, Guangdong 518060, China.
authors.forename: Muqing
authors.initials: M
authors.lastname: Lin
authors.affiliation: Department of Cell biology and Neuroscience, University of California, Riverside, Riverside, CA 92521, USA, Department of Biomedical Engineering, School of Medicine, Shenzhen University, Guangdong 518060, China, Department of Molecular and Medical Pharmacology and Institute for Molecular Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA and Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Monika
authors.initials: M
authors.lastname: Garcia
authors.affiliation: Department of Molecular and Medical Pharmacology and Institute for Molecular Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA and.
authors.forename: David
authors.initials: D
authors.lastname: Mulholland
authors.affiliation: Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Lilly
authors.affiliation: Department of Cell biology and Neuroscience, University of California, Riverside, Riverside, CA 92521, USA, Department of Biomedical Engineering, School of Medicine, Shenzhen University, Guangdong 518060, China, Department of Molecular and Medical Pharmacology and Institute for Molecular Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA and Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA manuela.martins@ucr.edu.
authors.forename: Manuela
authors.initials: M
authors.lastname: Martins-Green
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001688:Biological Products; D054377:Chemokine CXCL12 / Q000378:metabolism; D004610:Ellagic Acid / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D006801:Humans; D008042:Linolenic Acids / Q000494:pharmacology*; D047311:Luteolin / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D001688:Biological Products; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D008042:Linolenic Acids; D019718:Receptors, CXCR4; D004610:Ellagic Acid; D051057:Proto-Oncogene Proteins c-akt; D047311:Luteolin; C519714:punicic acid