Inositol hexaphosphate suppresses growth and induces apoptosis in prostate carcinoma cells in culture and nude mouse xenograft: PI3K-Akt pathway as potential target.

Abstract

Constitutive activation of phosphoinositide 3-kinase (PI3K)-Akt pathway transmits growth-regulatory signals that play a central role in promoting survival, proliferation, and angiogenesis in human prostate cancer cells. Here, we assessed the efficacy of inositol hexaphosphate (IP6) against invasive human prostate cancer PC-3 and C4-2B cells and regulation of PI3K-Akt pathway. IP6 treatment of cells suppressed proliferation, induced apoptosis along with caspase-3 and poly(ADP-ribose) polymerase (PARP) cleavage, and inhibited constitutive activation of Akt and its upstream regulators PI3K, phosphoinositide-dependent kinase-1 and integrin-linked kinase-1 (ILK1). Downstream of Akt, IP6 inhibited the phosphorylation of glycogen synthase kinase-3alpha/beta at Ser(21/9) and consequently reduced cyclin D1 expression. Efficacy studies employing PC-3 tumor xenograft growth in nude mice showed that 2% (w/v) IP6 feeding in drinking water inhibits tumor growth and weight by 52% to 59% (P < 0.001). Immunohistochemical analysis of xenografts showed that IP6 significantly reduces the expression of molecules associated with cell survival/proliferation (ILK1, phosphorylated Akt, cyclin D1, and proliferating cell nuclear antigen) and angiogenesis (platelet endothelial cell adhesion molecule-1 or CD31, vascular endothelial growth factor, endothelial nitric oxide synthase, and hypoxia-inducible factor-1alpha) together with an increase in apoptotic markers (cleaved caspase-3 and PARP). These findings suggest that, by targeting the PI3K-ILK1-Akt pathway, IP6 suppresses cell survival, proliferation, and angiogenesis but induces death in prostate cancer cells, which might have translational potential in preventing and controlling the growth of advanced and aggressive prostate cancer for which conventional chemotherapy is not effective.

• Authors: Mallikarjuna Gu, Srirupa Roy, Komal Raina, Chapla Agarwal, Rajesh Agarwal
• Journal: Cancer research (Cancer Res) Vol. 69 Issue 24 Pg. 9465-72 (Dec 15 2009) ISSN: 1538-7445 [Electronic] United States
• PMID: 19920184 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• DNA, Neoplasm
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Vascular Endothelial Growth Factor A
• Cyclin D1
• Phytic Acid
• Nitric Oxide Synthase Type III
• integrin-linked kinase
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Apoptosis (drug effects)
• Cell Growth Processes (drug effects)
• Cyclin D1 (biosynthesis)
• DNA, Neoplasm (metabolism)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Male
• Mice
• Mice, Nude
• Neovascularization, Pathologic (drug therapy, metabolism, pathology)
• Nitric Oxide Synthase Type III (biosynthesis)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphorylation (drug effects)
• Phytic Acid (pharmacology)
• Prostatic Neoplasms (blood supply, drug therapy, enzymology, pathology)
• Protein Serine-Threonine Kinases (biosynthesis)
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction (drug effects)
• Vascular Endothelial Growth Factor A (biosynthesis)
• Xenograft Model Antitumor Assays