TY - JOUR
T1 - Zyflamend® -mediated inhibition of human prostate cancer PC3 cell proliferation
T2 - Effects on 12-LOX and Rb protein phosphorylation
AU - Yang, Peiying
AU - Cartwright, Carrie
AU - Chan, Diana
AU - Vijjeswarapu, Mary
AU - Ding, Jibin
AU - Newman, Robert A.
PY - 2007/2
Y1 - 2007/2
N2 - The multiherb anti-inflammatory product Zyflamend was investigated for its anti-proliferative 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 PGE2 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 G2/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.
AB - The multiherb anti-inflammatory product Zyflamend was investigated for its anti-proliferative 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 PGE2 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 G2/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.
KW - 12-lipoxygenase
KW - Anti-proliferative
KW - Prostate cancer
KW - Zyflamend
KW - pRb protein
UR - http://www.scopus.com/inward/record.url?scp=34247348643&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34247348643&partnerID=8YFLogxK
U2 - 10.4161/cbt.6.2.3624
DO - 10.4161/cbt.6.2.3624
M3 - Article
C2 - 17218785
AN - SCOPUS:34247348643
SN - 1538-4047
VL - 6
SP - 228
EP - 236
JO - Cancer Biology and Therapy
JF - Cancer Biology and Therapy
IS - 2
ER -