Reduction of CWR22 prostate tumor xenograft growth by combined tamoxifen-quercetin treatment is associated with inhibition of angiogenesis and cellular proliferation.
Combination chemotherapy is increasingly practiced for the treatment of malignant prostate cancers. The aim of this study was to evaluate the in vivo efficacy of combined tamoxifen and quercetin in prostate tumor xenografts. Severe combined immune deficient (SCID) mice inoculated with CWR22 prostate tumor cells were treated with either tamoxifen (10 mg/kg/week), quercetin (200 mg/kg/day) or combined tamoxifen-quercetin for 28 days. Tamoxifen or quercetin alone exhibited a moderate antitumor activity. Tamoxifen decreased the Ki-67 index by 52.4%, reduced the vascular endothelial growth factor (VEGF) 121 and VEGF165 mRNA by 18.6 and 21.8%, respectively, and suppressed the blood vessel formation, while quercetin modulated the expression and phosphorylation of cdc-2 and cyclin B1, and inhibited the Ki-67 index by 66.0%. Combined tamoxifen-quercetin effectively delayed the appearance of tumors, inhibited the final tumor volume by 73.3% and reduced the endpoint tumor weight by 67.1% (p<0.05). The Ki-67 index, VEGF121, VEGF165 mRNA and microvessel density (MVD) were decreased by 66.9, 22.1, 40.1 and 59.0%, respectively, by the combined treatment. These findings indicate that tamoxifen inhibits CWR22 prostate tumor by modulating the angiogenesis and its antineoplastic effects can be potentiated by combined use with quercetin.
Ma
Zeng-Shuan
ZS
Laboratory of Molecular Endocrinology, Division of Cellular and Molecular Research, National Cancer Center of Singapore, Singapore 169610.
Huynh
Thanh Hoa
TH
Ng
Chee Pang
CP
Do
Phuc Tien
PT
Nguyen
Thanh Hung
TH
Huynh
Hung
H
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D016203:CDC2 Protein Kinase / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D019926:Cyclin B / Q000378:metabolism; D056744:Cyclin B1; D004359:Drug Therapy, Combination; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008833:Microcirculation; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000517:prevention & control*; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000098:blood supply* / Q000473:pathology / Q000628:therapy*; D011794:Quercetin / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013629:Tamoxifen / Q000627:therapeutic use*; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
D018931:Antineoplastic Agents, Hormonal; C534699:CCNB1 protein, human; C534700:Ccnb1 protein, mouse; D019926:Cyclin B; D056744:Cyclin B1; D019394:Ki-67 Antigen; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D013629:Tamoxifen; D011794:Quercetin; D016203:CDC2 Protein Kinase