Inositol is a substance found naturally in cantaloupe, citrus fruit, and many fiber-rich foods such as beans, brown rice, corn, sesame seeds, and wheat bran. It is also sold in supplement form and used as a complementary therapy to treat a wide range of medical conditions, including metabolic and mood disorders. Inositol is often referred to as vitamin B8, but it is not actually a vitamin. Inositol also has antioxidant properties that fight the damaging effects of free radicals in the brain, circulatory system, and other body tissues. They are generally considered safe if taken appropriately.
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Scarpa 14, Rome, Italy. Inositols myo-inositol and inositol hexakisphosphate exert a wide range of critical activities in both physiological and pathological settings.
Deregulated inositol metabolism has been recorded in a number of diseases, including cancer, where inositol modulates different critical pathways. Additionally, Akt activation is severely impaired upon inositol addition. Inositols interfere also with the cytoskeleton by upregulating Focal Adhesion Kinase and E-cadherin and decreasing Fascin and Cofilin, two main components of pseudopodia, leading hence to invasiveness impairment. Overall, these effects enable inositols to remodel the cytoskeleton architecture.
Inositol myo-Ins and its phosphate metabolites exert a wide range of critical activities in both physiological and pathological settings. Indeed, deregulation of inositol metabolism has been extensively investigated in several illnesses, including neurological disorders [ 1 ], polycystic ovary syndrome [ 2 ], and metabolic diseases [ 3 ]. In the wake of the renewed interest for inositol phosphates InsPs and other inositol-based compounds, studies on the anticancer properties of both inositol hexakisphosphate InsP6 and myo-Ins have gained momentum during the last decades.
InsP6 inhibits growth and invasiveness of a number of cancer types, while both InsP6 and myo-Ins have been demonstrated to display significant chemopreventive effects both in vitro and in vivo. Furthermore, inositols have been involved in modulating unexpected processes, including mRNA transcription, chromatin remodeling, cytoskeleton configuration, and p53 activity, just to mention a few.
Therefore, these new findings prompted reassessing under a new light the putative role of both myo-Ins and InsP6 in carcinogenesis.
Since the early eighties [ 4 ], it has been recognized that wide variation in cancer incidence among different countries around the world can primarily be ascribed to environmental factors, among which diet is likely the most important [ 5 ]. This evidence is very strong for some cancers, like breast, prostate, and colon tumors, where differences in tumor incidence across countries have been mainly ascribed to their respective dietary habits [ 6 ].
Several investigations led support to this hypothesis [ 9 ], even if some inconsistencies have been recorded [ 10 ]. Yet, such association is probably a too simplistic one, given that fibers could not be the sole putative preventive factor.
Indeed, colon cancer incidence has been shown to differ significantly among groups consuming approximately the same amount of fibers [ 11 ].
These findings indicate that to assess the correlation between diet and cancer properly we should evaluate the consumption of specific components rather than focusing on the overall fiber intake. Both epidemiological and molecular investigations have indeed provided valuable data suggesting that distinct dietary components may exert specific anticancer activities.
Among those nutrients, compelling evidence gathered to date has evidenced that lignans, polyphenolic acids, stilbenes, bioflavonoids, phytic acid, and inositols exert unquestionable anticancer effects [ 12 , 13 ].
Moreover, it has been observed that only the consumption of fibers with high content of phytic acid is inversely correlated with colon cancer [ 14 ].
InsP6 is contained mainly in cereals, legumes, and oilseed [ 15 ]. The presence of a phosphate group in positions 1, 2, and 3 axial-equatorial axis confers unique properties to it as this configuration provides a specific chelating capacity regarding polyvalent cations, including iron and other potentially toxic elements Ni, Zn, Cu, and even Uranium [ 16 , 17 ].
This property makes InsP6 an excellent chelator of many potentially harmful trace elements that have been shown to cause deleterious effects in humans [ 18 ]. Moreover, InsP6 capacity in blocking hydroxyl radical formation makes phytic acid a strong physiological antioxidant [ 19 ]. Insofar as InsP6 is often referred to as an antinutrient [ 20 ] responsible for iron deficiencies mostly in underdeveloped countries, it should be emphasized that InsP6 displays its antinutritional effects only when the diet is already deprived of trace elements [ 21 ].
Dietary InsP6 is mainly digested in the gut by bacterial phytases and phosphatase [ 22 ], thus releasing myo-Ins and other inositol phosphates InsPs. Yet, a variable fraction of dietary IP6 is directly absorbed as such and can be recovered in plasma and urine [ 23 ], even if this assumption has been subject of controversy [ 24 , 25 ].
How appropriate the bioavailability of myo-Ins and InsP6 in western alimentary regimens is still constitutes a matter of debate [ 28 , 29 ]. Furthermore, assessment of myo-Ins requirements is further complicated by the fact that a significant amount of inositol is endogenously synthesized from glucose. Both enzymes are inducible in response to the specific tissue requirements, thus explaining why myo-Ins concentrations differ so greatly among different tissues and physiological conditions [ 31 ].
After cellular internalization through endocytosis InsP6 is partially dephosphorylated yielding myo-inositol and inositol phosphates, mainly InsP5 [ 32 ]. However, free myo-Ins is actively transported into cells by a means of complex transport system.
Within cells myo-Ins is converted into inositol phospholipids phosphatidylinositol, PI, and phosphatidylinositol phosphate s , , inositol-glycans IPGs , inositol phosphates InsPs, including InsP6 , and pyrophosphates PP-IPs , according to a complex network extensively reviewed elsewhere [ 33 , 34 ]. Several studies have investigated the inhibitory activity of InsP6 on cancer cells from both animals and humans.
Results are unambiguous and show that InsP6 induces G 1 phase arrest and abridges S phase of cancer cells, mainly by modulation of cyclins, upregulation of p53, p57, , and , and downregulation of phosphorylated pRb [ 35 — 37 ]. Consequently, in InsP6-treated cancer cells, a significant downregulation of genes involved in cell cycle advancement like c- myc , cyclin H, and FUSE and an upregulation of those activated during cycle inhibition CSK2, p57, and Id-2 have been observed [ 38 ].
Similar results have been obtained in other cancers, even though subtle differences have been recorded among different cell lines [ 40 , 41 ]. Early studies have suggested that InsP6 effect is rather cytostatic than cytotoxic [ 43 , 44 ]. However, further investigation demonstrated that InsP6 had unequivocal apoptotic effects on both solid and haematogenous tumors. This apoptotic effect is frequently associated with growth inhibition [ 35 , 51 ] and ascertaining whether both effects occur independently from each other still needs to be investigated.
Additionally, InsP6 has been shown to synergize with both doxorubicin and tamoxifen in inhibiting breast cancer growth, namely, in drug-resistant cancer cell lines [ 52 ].
This result implies that InsP6 may counteract drug resistance frequently displayed by tumor cells and should therefore be considered a useful adjunct in delivering conventional anticancer drugs. On the contrary, myo-Ins has been shown to have only a minimal proapoptotic activity and to induce a mild decrease in growth proliferation in colon, breast, soft tissue, and lung tumors [ 53 ].
Yet, myo-Ins is able to significantly synergize with InsP6, both in vitro and in vivo , in inducing cancer inhibition [ 54 ]. However, some results hint at a more subtle and complex role for inositol and its phosphate derivatives. In some circumstances, instead of apoptosis or growth inhibition, cell differentiation occurs after InsP6 treatment. Induction of differentiation in human erythroleukemia cells was preliminarily evidenced following InsP6 and subsequently in several other cancers, including rhabdomyosarcoma and breast, colon, and prostate tumors [ 55 — 57 ].
Why cancer cells respond so differently following InsP6 administration is poorly understood. It can be hypothesized that other factors, namely, other inositol phosphate derivatives, may participate in such processes, thereby driving the final output into diverse fates [ 58 ]. Yet, the contribution of context-dependent cues in modulating InsP6 effects cannot be discarded. Inhibition of cell proliferation and induction of apoptosis have been recorded in numerous cancer cell lines after InsP6 treatment.
A crucial factor in both issues is represented by p53 activity and the subsequent selective pathways triggered downstream of p InsP6 increases p53 levels severalfold at both mRNA and protein levels [ 47 , 59 ]. However, consistent data suggest that p53 is not mandatory for triggering InsP6-related effects, as apoptosis and inhibition of cell growth have been both observed in cancer cells lacking p53 [ 60 ]. On the contrary, p27 and p21 should be considered as essential molecular target of InsP6, given that the simultaneous knockdown of both p21 and p27 completely abrogates the anticancer effects of InsP6 [ 51 ].
By analogy, myo-Ins has been proven to reduce lung cancer incidence in mouse lacking p53 and treated with N-nitrosomethylurea [ 61 ]. Yet, a very recent paper demonstrated that oral myo-Ins does not suppress cancer development in p53 knockout mice [ 62 ], while evidence about the proapoptotic effect of myo-inositol is still inconclusive even in presence of p Thereby the question is still open and further studies are warranted to understand whether p53 activity is effectively required in mediating anticancer effects displayed by both InsP6 and myo-Ins.
Downstream of p53 InsP6 has been demonstrated to reduce prosurvival factors and to upregulate caspases and other components of the proapoptotic BCL-2 family [ 63 — 66 ].
NF-kB is a pivotal factor involved in fostering both survival pathways and the epithelial-mesenchymal transition EMT. Therefore, targeting NF-kB is currently deemed a promising approach in cancer management.
As observed with other natural compounds grape seed extracts, melatonin , the apoptotic effect triggered by inositol derivatives seems to be specific for cancer cells, given that both InsP6 and myo-Ins did not promote apoptosis in normal cells. Therefore, why normal and cancerous cells respond differently to both InsP6 and myo-inositol still deserves to be explained in detail.
PI3K triggers activation of Akt kinases through direct binding to the pleckstrin homology domain and the subsequent phosphorylation of Akt at two conserved residues. Hence, activated Akt modulates the function of numerous substrates involved in the regulation of cell survival, cell cycle progression, and cellular growth, eventually enabling cancer cells to become more aggressive [ 72 ].
It is therefore worth noting that both InsP6 and myo-Ins significantly reduce PI3K expression at both mRNA and protein levels [ 73 ] and Akt activation by inhibiting its phosphorylation [ 74 , 75 ].
Inhibition of PI3K activity and subsequent blocking of PKC and mitogen-activated kinases MAPK have been so far documented by several in vitro [ 76 — 78 ] and in vivo chemopreventive studies [ 79 , 80 ].
Furthermore, inositol-treated cells underwent profound cytoskeleton remodeling [ 75 ]. Overall, these data indicated that myo-Ins inhibits the principal molecular pathway supporting EMT in cancer cells. The ability of cancer to metastasize relies primarily on the invasiveness and increased motility of tumor cells.
It is therefore worth noting that, by blocking EMT, myo-Ins significantly hampers both motility and invasiveness of breast cancer cells. This effect is likely to be ascribed to cytoskeleton remodeling and to the concomitant inhibition of metalloproteinases MMPs release [ 75 ]. Similarly, InsP6 significantly reduces the number of lung metastatic colonies in a mouse metastatic tumor model [ 82 ], while in MDA-MB breast cancer cells this effect is mediated by reduced adhesion and MMPs release [ 83 , 84 ].
Increased expression of the aforementioned molecules has been demonstrated to be associated with carcinogenesis in numerous tissues, chiefly in colon cancer [ 86 ].
Eventually, this study demonstrated that InsP6 administration markedly suppressed in a dose-dependent manner the incidence of cancer in male Sprague Dawley rats when compared to controls. Moreover, InsP6 counteracts the proliferative response following inflammatory injury by inhibiting cyclin D1 and histone H3 expression [ 88 ]. Such inhibitory effects on inflammatory markers may not be confined to epithelial cells but should also probably involve the surrounding microenvironment.
Indeed, both InsP6 and myo-Ins have been demonstrated to prevent pulmonary fibrosis, breast density, and chronic inflammatory damage, likely by influencing the crosstalk among cells and their milieu [ 89 — 91 ]. Indeed, myo-Ins mitigates colonic epithelium inflammation as well as inflammatory consequences on colon stromal cells during microbial infections [ 93 , 94 ]. Furthermore, InsP6 has been shown to exert valuable effects on fibroblasts by blocking the syndecan-4 dependent focal adhesion and microfilament bound [ 95 ].
Syndecan-4 is a heparan sulphate proteoglycan embedded into cellular membranes, where it regulates cell-matrix interactions by interfering with cytoskeleton proteins and integrins.
Indeed, in human mammary cancer cell lines, cell adhesion to extracellular matrix was decreased after InsP6 treatment [ 84 ]. InsP6 disrupts such interaction, thus inhibiting the FGF-based signaling [ 96 ]. Inositol-related effects on the cell milieu also involve modulation of angiogenesis. Formation of new blood vessels is required for sustaining cancer growth and invasiveness.
Disruption of the structural relationships among cancer cells and their microenvironment promotes neoangiogenesis, mainly through the release of vascular endothelial growth factor VEGF. InsP6 negatively modulates VEGF release from tumor cells [ 45 ] and impairs endothelial cells growth [ 97 ]. Overall, these data suggest that inositol and its phosphate derivatives exert complex biological functions involving both cells and stromal factors.
Yet, given the entrenched correlations occurring among cells and microenvironment during carcinogenesis [ , ] the stromal effects of both InsP6 and myo-Ins deserve to be still fully investigated. Myo-inositol and its isomer D-chiro-inositol D-chiro-Ins participate in both insulin and glucose metabolisms, and deregulated myo-Ins metabolism has been documented in several conditions associated with diabetes or insulin resistance [ 3 ].
Indeed, low levels of inositol have been observed in biological fluids and insulin target tissues muscle, liver, and fat , frequently associated with excessive myo-Ins renal excretion, while low intracellular levels of myo-Ins have been detected in insulin insensitive tissues [ ].
When insulin binds to its receptor, two distinct inositol-phosphoglycans IPGs , incorporating either myo-Ins or D-Chiro-Ins IPG-A and IPG-P , are released by insulin-stimulated hydrolysis of glycosyl-phosphatidylinositol lipids located on the outer leaflet of the cell membrane. IPGs affect intracellular metabolic processes, namely, by activating key enzymes controlling the oxidative and nonoxidative metabolism of glucose and acting as insulin-mimetic when administered in vivo in normal or diabetic rats [ ].
Glycan derivatives of inositol significantly reduce insulin resistance and promote appropriate glucose metabolism [ ]. Given that myo-Ins may efficiently counteract insulin resistance and its metabolic complications [ ], it is tempting to speculate that it may also prevent IGF-1 increase associated with insulin resistance.
As both insulin resistance and IGF-1 are linked to increased cancer risk [ ], it is conceivable that myo-Ins modulation of insulin activity may efficiently contribute to reducing cancer risk. Indeed, InsP6 has been already shown to inhibit the IGF-1 receptor pathway-mediated sustained growth in cancer cells [ 85 ].
It is therefore tempting to speculate if inositol addition can antagonize cancer development by normalizing glucose metabolism in cancer cells, another matter that eventually still needs to be fully investigated.
Broad Spectrum Anticancer Activity of Myo-Inositol and Inositol Hexakisphosphate
Metrics details. Patients with invasive ductal breast cancer where polychemotherapy was indicated were monitored in the period from Fourteen patients in the same stage of ductal invasive breast cancer were involved in the study, divided in two randomized groups. In both groups of patients the same laboratory parameters were monitored.
The Health Benefits of Inositol
Scarpa 14, Rome, Italy. Inositols myo-inositol and inositol hexakisphosphate exert a wide range of critical activities in both physiological and pathological settings. Deregulated inositol metabolism has been recorded in a number of diseases, including cancer, where inositol modulates different critical pathways. Additionally, Akt activation is severely impaired upon inositol addition. Inositols interfere also with the cytoskeleton by upregulating Focal Adhesion Kinase and E-cadherin and decreasing Fascin and Cofilin, two main components of pseudopodia, leading hence to invasiveness impairment. Overall, these effects enable inositols to remodel the cytoskeleton architecture.
Protection Against Cancer by Dietary IP6 and Inositol
Ivana Vucenik, AbulKalam M. Inositol hexaphosphate IP 6 is a naturally occurring polyphosphorylated carbohydrate that is present in substantial amounts in almost all plant and mammalian cells. It was recently recognized to possess multiple biological functions. A striking anticancer effect of IP 6 was demonstrated in different experimental models.