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Notes / Thoughts

  • I couldn’t find much on Akt inhibition in normal cells. It may reduce Akt and mTOR in normal cells, and that might inhibit gains from exercise.
  • Might be best to take in large, continued doses during fasting to maximize anti cancer effect

Info

  • antioxidant / chelator
  • anticancer (via prevention (chelation), Akt/mTOR reduction, glycolysis reduction, MAPK inhibition)
  • anti-platelet aggregation
  • lipid lowering
  • insulin secretion modulation
  • anti-calcium oxalate crystals

notes
Akt promotes cyclin D1 translation via indirect activation of mTOR

wikipedia on MAPK
The MAPK/ERK pathway (also known as the Ras-Raf-MEK-ERK pathway) is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell.
When one of the proteins in the pathway is mutated, it can become stuck in the "on" or "off" position, which is a necessary step in the development of many cancers.

see anaturalhealingcenter.com

  • IP6 functions as an antioxidant by chelating divalent cations such as copper and iron, preventing the generation of reactive oxygen species responsible for cell injury and carcinogenesis
  • 3 Recently, both in vivo and in vitro studies utilizing IP6 have revealed a significant anticancer activity with a variety of tumor types, possibly via inhibition of tumor cell growth and differentiation.4 In vitro studies with colon, liver, and rhabdomyosarcoma cell lines, and animal models of mammary, colon, intestinal, and liver cancer, as well as rhabdomyosarcoma, have all demonstrated IP6’s anticancer properties.
  • anti-platelet aggregating and lipid-lowering effect
  • inhibition of HIV-1 virus replication
  • modulation of insulin secretion in pancreatic beta cells
  • and inhibition of urinary calcium oxalate crystallization, thereby preventing renal stone development.
  • IP6 decreased S phase and arrested cells in the G0/G1 phase of the cell cycle. A significant decrease in the expression of proliferation markers indicated IP6 disengaged cells from actively cycling.10 In addition
  • IP6 has been shown to enhance NK-cell activity, thereby boosting NK-cell cytotoxicity

Anti Cancer Proliferation

Metabolomics uncovers a link between inositol metabolism and osteosarcoma metastasis.
IP6 exposures had modest to minimal effects on cell proliferation, we observed reduced cellular glycolysis, down-regulation of PI3K/Akt signaling and suppression of OS metastatic progression
! Importantly, it is affecting the primary engine of cancer – glycolysis.

Onset of the lymphocytic infiltration and hyperplasia preceding the proliferation in F1 mouse lungs from the N-ethyl-N-nitrosourea exposed mothers: Prevention during the lactation period by inositol hexaphosphate.
IP6 administration to the predisposed mothers prevented the proliferation, inflammation and enhanced apoptosis in F1 lung as showed by a reduction in PCNA, NF-κB (p50), IL-6, COX-2, pSTAT3, STAT3, miR-155 and increase in caspases, cleavage of poly (ADP-ribose) polymerase.
IP6 administration also inhibited the activation of Akt and cyclin D1.

Inositol hexaphosphate downregulates both constitutive and ligand-induced mitogenic and cell survival signaling, and causes caspase-mediated apoptotic death of human prostate carcinoma PC-3 cells.
Mechanistic studies showed that biological effects of IP6 were associated with inhibition of both constitutive and ligand-induced Akt phosphorylation together with a decrease in total Akt levels, but a differential inhibitory effect on MAPKs extra cellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal protein kinase (JNK1/2), and p38 under constitutive and ligand-activated conditions. Under similar condition, IP6 also inhibited AP-1 DNA-binding activity and decreased nuclear levels of both phospho and total c-Fos and c-Jun.
Together, these findings for the first time establish IP6 efficacy in inhibiting aberrant EGF receptor (EGFR) or IGF-1 receptor (IGF-1R) pathway-mediated sustained growth promoting and survival signaling cascades in advanced and androgen-independent human PCa PC-3 cells

Inositol hexakisphosphate kinases induce cell death in Huntington disease.
inositol hexakisphosphate kinase type 2 (InsP(6)K2), which converts inositol hexakisphosphate to inositol pyrophosphate diphosphoinositol pentakisphosphate, mediates apoptotic cell death via its translocation from the nucleus to the cytoplasm
– interesting mechanism wherein IP6 causes apoptosis

Inositol hexaphosphate limits the migration and the invasiveness of colorectal carcinoma cells in vitro.
These results indicated that IP6 has potential to modulate the migration ability and expression of markers associated with invasion in SW620 cells

Inositol Hexaphosphate Inhibits Proliferation and Induces Apoptosis of Colon Cancer Cells by Suppressing the AKT/mTOR Signaling Pathway.
Based on these studies it may be concluded that InsP6 can reduce proliferation and induce apoptosis through inhibition of the AKT/mTOR pathway and mTOR effector followed by modulation of the expression and activity of several key components of these pathways in colon cancer cells.

Inositol hexaphosphate hydrolysate competitively binds to AKT to inhibit the proliferation of colon carcinoma.
IP4 and IP5, the probable primary constituents of the 20-30% degree of hydrolysis hydrolysates of IP6, inhibited the proliferation of SW620 cells by competitively inhibiting the AKT protein.

Inositol hexaphosphate suppresses colorectal cancer cell proliferation via the Akt/GSK-3β/β-catenin signaling cascade in a 1,2-dimethylhydrazine-induced rat model
In conclusion, the anti-proliferative effect of IP6 may be related to crosstalk between the PI3K/Akt and Wnt pathways, revealing a potential mechanism of CRC inhibition by IP6 in our model.

ANTIPROLIFERATIVE EFFECT OF INOSITOL HEXAPHOSPHATE ON HUMAN SKIN MELANOMA CELLS IN VITRO.
The results demonstrate the antiproliferative and cytotoxic properties of IP6 in a wide range of concentrations on human A2058 melanoma cells

In vitro regulation of cell growth and angiogenesis by inositol hexaphosphate in bladder cancer.
dietary polyphosphorylated carbohydrate IP6 significantly decreased cellular growth by anti-angiogenic mechanisms.

PI3K/Akt Pathway and miR-21 are Involved in N-Ethyl-N-Nitrosourea-Induced F1 Mouse Lung Tumorigenesis: Effect of Inositol Hexaphosphate.
Akt activation also enhanced the expression of cyclin D1, cyclooxygenase-2 (COX-2), nuclear factor-κB (NF-κBp50), and mammalian target of rapamycin (mTOR). IP6-fed F1 mice showed reduced tumorigenesis along with reduced expression of the PI3K/Akt pathway miR-21 and downstream targets. The PI3K/Akt pathway and miR-21 are involved in transplacental lung tumorigenesis, whereas IP6 seemed to affect lung tumorigenesis by suppressing the expression of the PI3K/Akt pathway in F1 mice.

https://www.ncbi.nlm.nih.gov/pubmed/12028025
Taken together, our results confirm the antiproliferative activity of IP(6) and suggest that it may have a specific antitumour effect also in chronic myeloid leukaemias, via active gene modulation.

Normal Cell Proliferation

Effect of dentine conditioning with phytic acid or etidronic acid on growth factor release, dental pulp stem cell migration and viability.
Cell proliferation significantly increased with time after ... IP6 treatment
... effective chelating agents on TGF-β release

Evaluation of in vitro and in vivo biocompatibility of a myo-inositol hexakisphosphate gelated polyaniline hydrogel in a rat model.

Differential response of MC3T3-E1 and human mesenchymal stem cells to inositol hexakisphosphate.
IP6 decreased gene expression of osteoblast markers and mineralization in MC3T3-E1 cells without negatively affecting cell viability and ALP activity, an increase in gene expression of ALP was observed in hUC-MSCs committed to the osteoblastic lineage
This increasing effect of IP6 on ALP mRNA expression levels was reversed by the addition of a selective inhibitor of IP6 kinase, suggesting that the effect of IP6 might be due through its pyrophosphorylated derivatives.
Rankl mRNA levels were decreased ... pointing to a paracrine effect on osteoclasts.

Misc

Inositol polyphosphates contribute to cellular circadian rhythms: Implications for understanding lithium’s molecular mechanism.
determined that IP6 increased rhythm amplitude and shortened period in NIH3T3 cells

“Phytate Inhibits Cardiovascular Calcifications”
– IP6 will definitely “reduce the body’s ability to absorb some minerals” when taken with meals… The trick is to take it on an empty stomach with a full glass of water. When taken properly, IP6 will chelate undesirable mineral excesses without disrupting overall mineral homeostasis.
– “It has been shown that the antinutritional effect of IP6 could be manifested only when large amounts of IP6 were consumed together with a diet poor in trace elements, but if essential minerals were present in the proper ratio with respect to IP6, there was no modification of mineral balance”