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: Lei Wang, Wenfang Li, Muqing Lin, Monika Garcia, David Mulholland, Michael Lilly, Manuela Martins-Green
• Journal: Carcinogenesis (Carcinogenesis) Vol. 35 Issue 10 Pg. 2321-30 (Oct 2014) ISSN: 1460-2180 [Electronic] England
• PMID: 25023990 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Antineoplastic Agents, Phytogenic
• Biological Products
• CXCR4 protein, mouse
• Chemokine CXCL12
• Cxcl12 protein, mouse
• Linolenic Acids
• Receptors, CXCR4
• Ellagic Acid
• Proto-Oncogene Proteins c-akt
• Luteolin
• punicic acid

Topics

• Animals
• Antineoplastic Agents, Phytogenic (pharmacology)
• Biological Products
• Chemokine CXCL12 (metabolism)
• Ellagic Acid (pharmacology)
• Endothelium, Vascular (drug effects, pathology)
• Humans
• Linolenic Acids (pharmacology)
• Luteolin (pharmacology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, SCID
• Neovascularization, Pathologic (drug therapy)
• Prostatic Neoplasms (drug therapy, pathology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Receptors, CXCR4 (metabolism)
• Signal Transduction (drug effects)
• Xenograft Model Antitumor Assays