Molecular mechanisms for the antitumor activity of inositol hexakisphosphate (IP6).
BACKGROUND
Inositol hexakisphosphate (IP6), a naturally occurring polyphosphorylated carbohydrate, has been reported to have significant in vivo and in vitro anticancer activity against numerous tumors. However, the molecular mechanism of the anticancer effect of IP6 has not been fully elucidated.


METHODS
Using K-562 human leukemia cells we analysed the induction of the erythroid differentiation program, as well as modulation of the gene expression profile of K-562 leukemia cells treated with IP6.


RESULTS
A single treatment with IP6 (0.75 or 5.0 mM) resulted in a time- and dose-dependent growth inhibition of K-562 cells and also activation of the erythroid differentiation program. K-562 cells expressed a concomitant differentiation after 12 hours of exposure. Possible molecular mechanisms and key signaling pathways, as well as gene expression behind this anticancer effect were examined using oligonucleotide microarrays and quantitative real-time PCR. Treatment with IP6 (750 microM, 5 mM) had a marked impact, resulting in early (60 min) and late (12 h) modulation of expression of about 1800 and 1200 transcripts (at p<0.05). Through microarray analysis, the anticancer effect of IP6 in K-562 was found to be associated with the modulation of multiple genes involved in immunity, Wnt and IGF pathways, PI3 kinase signaling and apoptosis. Using selected subsets of genes, the microarray hits could be validated by Q-PCR. A 2-fold upregulation of the apoptosis pathway, measured using the BAX/BCL-2 ratio was observed for 12 hours. IP6 (5 mM) induced up to 6-fold increases in differentiation measured by hemoglobin synthesis, yielding up to 70% of benzidine-positive cells at 120 hours.


CONCLUSIONS
The results of this study show that IP6 is a strong inducer of differentiation (cytostatic effect) and a moderately strong inducer of apoptosis (cytotoxic effect). Evidence has been provided to show that the growth inhibitory effects of IP6 are mediated through the modulation of key signaling pathways.
Bozsik
Anikó
A
National Institute of Oncology, Department of Molecular Genetics, Budapest, H-1122, Hungary.
Kökény
Szabolcs
S
Olah
Edith
E
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001560:Benzidines; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016000:Cluster Analysis; D041905:Erythroid Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D020014:K562 Cells; D020411:Oligonucleotide Array Sequence Analysis; D010833:Phytic Acid / Q000494:pharmacology*; D015203:Reproducibility of Results
D000970:Antineoplastic Agents; D001560:Benzidines; C029876:benzidine; D010833:Phytic Acid