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Myo ‐InositolTrisPyroPhosphate Treatment Leads to HIF‐1α Suppression and Eradication of Early Hepatoma Tumors in Rats
Author(s) -
Aprahamian Marc,
Bour Gaétan,
Akladios Chérif Y.,
Fylaktakidou Konstantina,
Greferath Ruth,
Soler Luc,
Marescaux Jacques,
Egly JeanMarc,
Lehn JeanMarie,
Nicolau Claude
Publication year - 2011
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201000619
Subject(s) - apoptosis , hepatocellular carcinoma , in vivo , hemoglobin , hypoxia (environmental) , vascular endothelial growth factor , cancer research , hypoxia inducible factors , doxorubicin , biology , pathology , chemistry , medicine , chemotherapy , oxygen , vegf receptors , biochemistry , microbiology and biotechnology , organic chemistry , gene
Abstract Myo ‐inositol trispyrophosphate (ITPP), a synthetic allosteric effector of hemoglobin, increases the regulated oxygen‐releasing capacity of red blood cells (RBCs), leading to suppression of hypoxia‐inducible factor 1α (HIF‐1α) and to down‐regulation of hypoxia‐inducible genes such as vascular endothelial growth factor (VEGF). As a consequence, tumor growth is markedly affected. The effect of weekly intravenous injection of ITPP on an orthotopic, syngenic rat hepatocellular carcinoma (HCC) model was compared to that for untreated animals and animals subjected to conventional Doxorubicin chemotherapy. The longitudinal examination of HCC was performed by microCT imaging, and the cellular and molecular changes were evaluated by histology and Western blotting analysis of HIF‐1α, VEGF, and caspase‐3 gene expression in the tumor and in the surrounding liver. Hematologic impact was evaluated by blood cell‐count measurement and determination of P50 (oxygen partial pressure for a 50 % oxygen saturation of hemoglobin). The HCC evaluation by microCT revealed a high potency of ITPP for tumor growth inhibition, thus allowing long‐term survival and even cure of almost all the treated animals. The P50 value of hemoglobin in RBCs underwent a shift of 30 % following ITPP injection. Under these conditions, HIF‐1α activity was strongly decreased, VEGF expression was down‐regulated, and apoptosis was induced in HCC and surrounding liver cells, as indicated by Caspase‐3 expression. ITPP did not affect hematologic parameters during treatment. The observations of in vivo tumor eradication suggest a significant clinical potential for ITPP in cancer therapy.