G0/G1 arrest and S phase inhibition of human cancer cell lines by inositol hexaphosphate (IP6)

University of Maryland, Baltimore, Baltimore, Maryland, United States
Anticancer research (Impact Factor: 1.83). 07/2001; 21(4A):2393-403.
Source: PubMed


Inositol hexaphosphate (InsP6 or IP6) has shown a striking anti-cancer activity in both in vivo and in vitro models. In an attempt to elucidate the mechanism(s) underlying the anti-neoplastic potential of IP6, we investigated its effect on cell cycle progression of MCF-7 estrogen receptor (ER)-positive and MDA-MB 231 ER-negative human breast cancer cell lines and HT-29 human colon cancer cells.
The anti-proliferative effect of IP6 was evaluated using dual-parameter flow cytometric measurements of DNA content, versus the incorporation of 5-bromo-2-deoxyuridine (BrdU) to determine cells actively synthesizing DNA. Combined analysis of the expression of cell cycle-related proteins, proliferation marker Ki-67 and proliferating cell nuclear antigen (PCNA) versus DNA content were used to determine the amount of proliferating cells in each phase, engaged in cell cycle transit.
After 3 days of treatment with 5 mM IP6, S-phase, as estimated by BrdU uptake, was significantly decreased in all three cell lines (p = 0.002). MCF-7 and HT-29 cells accumulated in the G0/G1 range of DNA contents (p = 0.002 and p = 0.001, respectively). MDA MB-231 cells transiently accumulated in G0/G1 only after 2 days (p = 0.01). There was a significant decrease in the percentage of Ki-67 expression in IP6-treated cells, from 82.8+/-3.0% to 66.8+/-4.2% in MCF-7 (p = 0.007), from 93.4+/-4.6% to 71.7+/-3.3% in MDA-MB 231 (p = 0.004), and from 95.2+/-1.2% to 73.5+/-2.5% in HT-29 cells (p = 0.002) respectively. PCNA expression levels were also significantly decreased by IP6 in all three cell lines (MCF-7 p = 0.0007; MDA-MB 231 p = 0.0006; HT-29 p = 0.0001).
These results show that IP6 controls the progression of cells through the cycle by decreasing S- phase and arresting cells in the G0/G1-phase of the cell cycle. A significant decrease in the expression of proliferation markers indicated that IP6 disengaged cells from actively cycling. Further investigations of cell cycle regulators may lead us to a better understanding of the mechanism(s) of the anti-neoplastic action of IP6.

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Available from: A.K. M Shamsuddin, May 08, 2014
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    • "Besides an antioxidant mechanism, other mechanisms, such as the suppression of p53 or the modulation of other cancer associated genes, may account for chemopreventive effects of IP6. Recently, G0/G1 arrest and S phase inhibition of human cancer cell lines by IP6 were reported (Sharma et al., 2003; El-Sherbiny et al., 2001). "
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    ABSTRACT: Chemoprevention is considered a rational strategy for dietary approaches to prevention of cancer. Multiple lines of evidence suggest that many of our dietary principles are able to intervene in the multistage carcinogenesis process and phytic acid (inositol hexaphosphate, IP6), a phytochemical present in a variety of plant species, has been shown to prevent various cancers, including those of the mammary gland, colon and liver. However, the mechanism of chemoprevention by IP6 has not been fully elucidated. In the present study, we examined the effects of inositol and/or IP6 supplementation on rat hepatocarcinogenesis initiated by diethylnitrosamine (DEN) and promoted by partial hepatectomy (PH). Supplementation with either inositol or IP6, or their combination, starting one week prior to administration of DEN, resulted in a significant decrease in both the area and the number of placental glutathione S-transferase positive (GST-P+) foci, a preneoplastic marker for DEN-initiated hepatocarcinogenesis. The administration of inositol and/or IP6 in drinking water caused marked enhancement in the glutathione S-transferase (GST) activity. In addition, the production of thiobarbituric acid reactive substances and the catalase activity were significantly reduced in rats supplemented with inositol and /or IP6. Based on these findings, it is likely that the chemopreventive effects of inositol and/or IP6 on rat hepatocarcinogenesis initiated by DEN and promoted by PH are associated with induction of GST activity and suppression of lipid peroxidation.
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