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Increasing the oxygen load by treatment with myo-inositol trispyrophosphate reduces growth of colon cancer and modulates the intestine homeobox gene Cdx2

Oncogene volume 32, pages 4313–4318 (2013)Cite this article

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Abstract

Preventing tumor neovascularisation is one of the strategies recently developed to limit the dissemination of cancer cells and apparition of metastases. Although these approaches could improve the existing treatments, a number of unexpected negative effects have been reported, mainly linked to the hypoxic condition and the subsequent induction of the pro-oncogenic hypoxia inducible factor(s) resulting from cancer cells’ oxygen starvation. Here, we checked in vivo on colon cancer cells an alternative approach. It is based on treatment with myo-inositol trispyrophosphate (ITPP), a molecule that leads to increased oxygenation of tumors. We provide evidence that ITPP increases the survival of mice in a model of carcinomatosis of human colon cancer cells implanted into the peritoneal cavity. ITPP also reduced the growth of subcutaneous colon cancer cells xenografted in nu/nu mice. In the subcutaneous tumors, ITPP stimulated the expression of the homeobox gene Cdx2 that is crucial for intestinal differentiation and that also has an anti-tumoral function. On this basis, human colon cancer cells were cultured in vitro in hypoxic conditions. Hypoxia was shown to decrease the level of Cdx2 protein, mRNA and the activity of the Cdx2 promoter. This decline was unrelated to the activation of HIF1α and HIF2α by hypoxia. However, it resulted from the activation of a phosphatidylinositol 3-kinases-like mitogen-activated protein kinase pathway, as assessed by the fact that LY294002 and U0126 restored high Cdx2 expression in hypoxia. Corroborating these results, U0126 recapitulated the increase of Cdx2 triggered by ITPP in subcutaneous colon tumor xenografts. The present study provides evidence that a chemical compound that increases oxygen pressure can antagonize the hypoxic setting and reduce the growth of human colon tumors implanted in nu/nu mice.

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Acknowledgements

This work was supported by the INSERM (France), NormOxys Inc (USA) and the Ligue contre la Cancer du Haut-Rhin (France). Ms Saandi was supported by the AICR (UK) and the Département of Mayotte (France).

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Author notes

  1. I Duluc and J-N Freund: These authors contributed equally to this work.

Authors and Affiliations

  1. INSERM U682, Strasbourg, France

    L Derbal-Wolfrom, T Saandi, M Aprahamian, E Martin, I Duluc & J-N Freund

  2. EA 4438 Physiopathologie et Médecine Translationnelle, Laboratoire de Biochimie et Biologie Moléculaire, CHU Hautepierre, Strasbourg, France

    E Pencreach

  3. NormOxys, Inc, Boston, MA, USA

    R Greferath, E Tufa & C Nicolau

  4. CNRS Fre3240, Service de Biophysique et Médecine Nucléaire, CHU Hautepierre, Strasbourg, France

    P Choquet

  5. ISIS, CNRS UMR 7006, 8 allée Gaspard Monge, Strasbourg, France

    R Greferath, E Tufa & J-M Lehn

  6. Friedman School of Nutrition Science, Tufts University, Boston, MA, USA

    C Nicolau

  7. Université de Strasbourg, Faculté de Médecine, Strasbourg, France

    L Derbal-Wolfrom, E Pencreach, T Saandi, M Aprahamian, E Martin, P Choquet, J-M Lehn, I Duluc & J-N Freund

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  1. L Derbal-Wolfrom
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  9. J-M Lehn
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  10. C Nicolau
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  11. I Duluc
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Corresponding author

Correspondence to J-N Freund.

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Competing interests

Drs Nicolau and Lehn have received compensation as members of the scientific advisory board and own stock in NormOxys Inc, which holds the patents on the applications of inositol trispyrrophosphate. Drs Greferath and Tufa have consulted for NormOxys Inc and have received compensations. Ms Derbal-Wolfrom was a recipient of a funding by NormOxys Inc. Ms Martin and Drs Aprahamian, Pencreach, Choquet, Duluc and Freund declare no potential conflict of interest.

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Derbal-Wolfrom, L., Pencreach, E., Saandi, T. et al. Increasing the oxygen load by treatment with myo-inositol trispyrophosphate reduces growth of colon cancer and modulates the intestine homeobox gene Cdx2. Oncogene 32, 4313–4318 (2013). https://doi.org/10.1038/onc.2012.445

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