In vivo suppression of hormone-refractory prostate cancer growth by inositol hexaphosphate: induction of insulin-like growth factor binding protein-3 and inhibition of vascular endothelial growth factor.
OBJECTIVE
Diet composition is an important etiologic factor in prostate cancer (PCA) growth and has significant impact on clinical PCA appearance. Because inositol hexaphosphate (IP6) is a dietary phytochemical present in cereals, soy, legumes, and fiber-rich foods, we evaluated efficacy of IP6 against PCA growth and associated molecular events.


METHODS
DU145 cells were injected into nude mice, and animals were fed normal drinking water or 1 or 2% IP6 in drinking water for 12 weeks. Body weight, diet, water consumption, and tumor sizes were monitored. Tumors were immunohistochemically analyzed for proliferating cell nuclear antigen, terminal deoxynucleotidyl transferase-mediated nick end labeling, and CD31. Tumor-secreted insulin-like growth factor binding protein (IGFBP)-3 and vascular endothelial growth factor (VEGF) were quantified in plasma by ELISA.


RESULTS
IP6 feeding resulted in suppression of hormone-refractory human prostate tumor growth without any adverse effect on body weight gain, diet, and water consumption during entire study. At the end of study, tumor growth inhibition by 1 and 2% IP6 feeding was 47 and 66% (P = 0.049-0.012) in terms of tumor volume/mouse and 40 and 66% (P = 0.08-0.003) in terms of tumor weight/mouse, respectively. Tumor xenografts from IP6-fed mice showed significantly (P < 0.001) decreased proliferating cell nuclear antigen-positive cells but increased apoptotic cells. Tumor-secreted IGFBP-3 levels were also increased up to 1.7-fold in IP6-fed groups. Additionally, IP6 strongly decreased tumor microvessel density and inhibited tumor-secreted VEGF levels.


CONCLUSIONS
IP6 suppresses hormone-refractory PCA growth accompanied by inhibition of tumor cell proliferation and angiogenesis and increased apoptosis. IP6-caused increase in IGFBP-3 and decrease in VEGF might have a role in PCA growth control.
Singh
Rana P
RP
Department of Pharmaceutical Sciences, University of Colorado Cancer Center, University of Colorado Health Sciences Center, Denver, Colorado, USA.
Sharma
Girish
G
Mallikarjuna
G U
GU
Dhanalakshmi
Sivanandhan
S
Agarwal
Chapla
C
Agarwal
Rajesh
R
D000821:Animal Feed; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007124:Immunoenzyme Techniques; D020287:In Situ Nick-End Labeling; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism / Q000517:prevention & control*; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D010833:Phytic Acid / Q000627:therapeutic use*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000517:prevention & control*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
D018972:Insulin-Like Growth Factor Binding Protein 3; D018809:Proliferating Cell Nuclear Antigen; D042461:Vascular Endothelial Growth Factor A; D010833:Phytic Acid