Inositol tripyrophosphate: a new membrane permeant allosteric effector of haemoglobin

Fylaktakidou, Konstantina C.; Lehn, Jean‐Maríe; Greferath, Ruth; Nicolau, Claude

doi:10.1016/j.bmcl.2005.01.064

Cited by 42 publications

(73 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…ITPP has been synthesized as a derivative of IP 6 with increased membrane permeability and the ability to lower Hb affinity for oxygen on free Hb as well as on whole blood [7]. Since pO 2 is an important regulator of angiogenesis, we hypothesized that, by facilitating oxygen availability at physiological pO 2 values, ITPP could act as an anti-angiogenic compound.…”

Section: Discussionmentioning

confidence: 99%

Anti‐angiogenic properties of myo‐inositol trispyrophosphate in ovo and growth reduction of implanted glioma

et al. 2007

Self Cite

View full text Add to dashboard Cite

We investigate here the anti-angiogenic properties of the synthetic compound myo-inositol trispyrophosphate (ITPP). By increasing oxy-haemoglobin dissociation, ITPP has the potential to counteract the effects of hypoxia, a critical regulator of angiogenesis and cancer progression. ITPP inhibited angiogenesis of the chorioallantoic membrane (CAM), as analyzed with an original program dedicated to automated quantification of angiogenesis in this model. ITPP also markedly reduced tumor progression and angiogenesis in an experimental model of U87 glioma cell nodules grafted onto the CAM. These results point out the potential of ITPP for the development of a new class of anti-angiogenic and anti-cancer compounds.

show abstract

Section: Discussionmentioning

confidence: 99%

Anti‐angiogenic properties of myo‐inositol trispyrophosphate in ovo and growth reduction of implanted glioma

et al. 2007

Self Cite

View full text Add to dashboard Cite

show abstract

“…features for the successful treatment of tumor hypoxia (11). Acting as an allosteric effector of hemoglobin, ITPP increases dissociation of O 2 from heme particularly under low pO 2 , creating antihypoxic potency (11).…”

Section: Myo-inositol Trispyrophosphate (Itpp) Is a Novel Molecule Thmentioning

confidence: 99%

“…Acting as an allosteric effector of hemoglobin, ITPP increases dissociation of O 2 from heme particularly under low pO 2 , creating antihypoxic potency (11). Additionally, its uptake seems to be tissue-specific towards erythrocytes (12).…”

Section: Myo-inositol Trispyrophosphate (Itpp) Is a Novel Molecule Thmentioning

confidence: 99%

Antihypoxic Potentiation of Standard Therapy for Experimental Colorectal Liver Metastasis through Myo-Inositol Trispyrophosphate

Limani¹,

Linecker²,

Kachaylo³

et al. 2016

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

PURPOSE: Tumor hypoxia activates hypoxia-inducible factors (Hifs), which induce a range of malignant changes including vascular abnormalities. Here, we determine whether inhibition of the hypoxic tumor response through myo-inositol trispyrophosphate (ITPP), a compound with antihypoxic properties, is able to cause prolonged vascular normalization that can be exploited to improve standardof-care treatment. EXPERIMENTAL DESIGN: We tested ITPP on two syngeneic orthotopic mouse models of lethal colorectal cancer liver metastasis. Tumors were monitored by MRI and analyzed for the hypoxic response and their malignant potential. A Hif activator and in vitro assays were used to define the working mode of ITPP. Hypoxic response and vasculature were re-evaluated 4 weeks after treatment. Finally, we determined survival following ITPP monotherapy, FOLFOX monotherapy, FOLFOX plus Vegf antibody, and FOLFOX plus ITPP, both overlapping and sequential. RESULTS: ITPP reduced tumor load, efficiently inhibited the hypoxic response, and improved survival. These effects were lost when mice were pretreated with a Hif activator. Its immediate effects on the hypoxic response, including an apparent normalization of tumor vasculature, persisted for at least 4 weeks after treatment cessation. Compared with FOLFOX alone, Vegf antibody combined with FOLFOX prolonged survival by <30%, whereas ITPP combined with FOLFOX extended survival by >140%, regardless of whether FOLFOX was given in overlap or after ITPP exposure. CONCLUSIONS: Our findings reveal a truly antihypoxic mechanism for ITPP and demonstrate the capacity of this nontoxic compound to potentiate the efficacy of existing anticancer treatment in a way amenable to clinical translation. Clin Cancer Res; 22(23); 5887-97. DOI: https://doi.org/10.1158/1078-0432. Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-125980 Accepted Version Originally published at: Limani, P; Linecker, M; Kachaylo, E; Tschuor, C; Kron, P; Schlegel, A; Ungethuem, U; Jang, J H; Georgiopoulou, S; Claude Nicolau, C; Lehn, J-M; Graf, R; Humar, B; Clavien, P-A (2016). Antihypoxic potentiation of standard therapy for experimental colorectal liver metastasis through myo-inositol trispyrophosphate. Clinical Cancer Research, 22 (23) Results. ITPP reduced tumor load, efficiently inhibited the hypoxic response, and improved survival. These effects were lost when mice were pretreated with a Hif activator. Its immediate effects on the hypoxic response, including an apparent normalization of tumor vasculature, persisted for at least four weeks after treatment cessation. Compared to FOLFOX alone, Vegf antibody combined with FOLFOX prolonged survival by <30%, whereas ITPP combined with FOLFOX extended survival by >140%, regardless of whether FOLFOX was given in overlap or after ITPP exposure. Conclusions.Our findings reveal a truly antihypoxic mechanism for ITPP and demonstrate the capacity of this nontoxic compound to potentiate the efficacy of existing antic...

show abstract

“…Previous efforts to modify RBC Hb affinity pharmacologically have been limited by the failure of effector molecules to cross RBC membranes (11,14), short duration of effects (19), and poor solubility in water (20). Because ITPP is both membrane permeant and readily soluble in water (15,16), we considered the possibility that ITPP would be absorbed after oral ingestion.…”

Section: Itpp Increases Exercise Capacity In Normalmentioning

confidence: 99%

“…Because at neutral pH, IP 6 is a partially dissociated polyanion bearing 8 negative charges (13), it is unable to cross the RBC membrane and ex vivo physical methods are required to load erythrocytes (11,14). However, we recently showed that myo-inositol trispyrophosphate (ITPP) hexasodium salt is capable of crossing the RBC plasma membrane and acting as an allosteric effector of Hb, shifting the oxyhemoglobin dissociation curve to higher oxygen pressures (pO 2 ) (15,16), and leading to a marked inhibition of blood vessel formation processes in vitro (16). Accordingly, we tested the hypothesis that systemic administration of ITPP would increase exercise capacity in normal mice and in mice with severe exercise limitation caused by reduced cardiac output as a result of myocardial failure.…”

mentioning

confidence: 99%

Enhanced exercise capacity in mice with severe heart failure treated with an allosteric effector of hemoglobin, myo -inositol trispyrophosphate

Biolo

Greferath

Siwik

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

A major determinant of maximal exercise capacity is the delivery of oxygen to exercising muscles. myo-Inositol trispyrophosphate (ITPP) is a recently identified membrane-permeant molecule that causes allosteric regulation of Hb oxygen binding affinity. In normal mice, i.p. administration of ITPP (0.5-3 g/kg) caused a dose-related increase in the oxygen tension at which Hb is 50% saturated (p50), with a maximal increase of 31%. In parallel experiments, ITPP caused a dose-related increase in maximal exercise capacity, with a maximal increase of 57 ؎ 13% (P ‫؍‬ 0.002). In transgenic mice with severe heart failure caused by cardiacspecific overexpression of G␣q, i.p. ITPP increased exercise capacity, with a maximal increase of 63 ؎ 7% (P ‫؍‬ 0.005). Oral administration of ITPP in drinking water increased Hb p50 and maximal exercise capacity (؉34 ؎ 10%; P < 0.002) in normal and failing mice. Consistent with increased tissue oxygen availability, ITPP decreased hypoxia inducible factor-1␣ mRNA expression in myocardium. It had no effect on myocardial contractility in isolated mouse cardiac myocytes and did not affect arterial blood pressure in vivo in mice. Thus, ITPP decreases the oxygen binding affinity of Hb, increases tissue oxygen delivery, and increases maximal exercise capacity in normal mice and mice with severe heart failure. ITPP is thus an attractive candidate for the therapy of patients with reduced exercise capacity caused by heart failure.hypoxia ͉ oxygen delivery

show abstract

Inositol tripyrophosphate: a new membrane permeant allosteric effector of haemoglobin

Cited by 42 publications

References 13 publications

Anti‐angiogenic properties of myo‐inositol trispyrophosphate in ovo and growth reduction of implanted glioma

Anti‐angiogenic properties of myo‐inositol trispyrophosphate in ovo and growth reduction of implanted glioma

Antihypoxic Potentiation of Standard Therapy for Experimental Colorectal Liver Metastasis through Myo-Inositol Trispyrophosphate

Enhanced exercise capacity in mice with severe heart failure treated with an allosteric effector of hemoglobin, myo -inositol trispyrophosphate

Contact Info

Product

Resources

About