Zyflamend-mediated inhibition of human prostate cancer PC3 cell proliferation: effects on 12-LOX and Rb protein phosphorylation.

Abstract

The multiherb anti-inflammatory product Zyflamend was investigated for its antiproliferative effects on PC3 human prostate cancer cells and eicosanoid metabolism in this prostate cancer cell line. Zyflamend produced a concentration-dependent inhibition of cloned COX-1, COX-2, and 5-LOX enzyme activities, with inhibition of 5-HETE production being greater than that of PGE(2) formation. Applied to intact PC3 cells, Zyflamend was found to be most potent against 12-LOX, followed by 5-LOX and then COX activities. The concentration-dependent inhibition of PC3 cell proliferation was associated with a selective G(2)/M arrest of the cell cycle and induction of apoptosis, as evidenced by flow cytometric staining of PC3 cells with annexin V. Zyflamend also produced a concentration-dependent down-regulation of 5-LOX and 12-LOX expression. Determination of cell signal transduction proteins demonstrated that Zyflamend produced an increase in p21 phosphorylation but down-regulated phosphorylation of retinoblastoma (Rb) protein. The decrease in pRb protein was shown to be due to 12-LOX inhibition and a decline in 12-HETE levels in the cells. Replenishing 12-HETE in Zyflamend-treated cells overcame the ability of this multiple herb product to inhibit cell proliferation, and concordantly, 12-HETE blocked Zyflamend's ability to down-regulate phosphorylation of Rb protein. We conclude that the effective control of human prostate cancer cell proliferation with Zyflamend is multi-mechanistic but, in part, involves regulation of aberrant tumor cell eicosanoid metabolism, especially on 5- and 12-LOX, as well as restoration of Rb tumor suppressor protein function through regulation of its phosphorylation status.

• Authors: Peiying Yang, Carrie Cartwright, Diana Chan, Mary Vijjeswarapu, Jibin Ding, Robert A Newman
• Journal: Cancer biology & therapy (Cancer Biol Ther) Vol. 6 Issue 2 Pg. 228-36 (Feb 2007) ISSN: 1538-4047 [Print] United States
• PMID: 17218785 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Lipoxygenase Inhibitors
• Plant Extracts
• Retinoblastoma Protein
• Zyflamend
• Arachidonate 12-Lipoxygenase
• Prostaglandin-Endoperoxide Synthases

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Arachidonate 12-Lipoxygenase (metabolism)
• Blotting, Western
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Down-Regulation (drug effects)
• Enzyme Inhibitors (pharmacology)
• Humans
• Lipoxygenase Inhibitors
• Male
• Phosphorylation (drug effects)
• Plant Extracts (pharmacology)
• Prostaglandin-Endoperoxide Synthases (drug effects)
• Prostatic Neoplasms (drug therapy)
• Retinoblastoma Protein (metabolism)
• Treatment Outcome