Stable tumor vessel normalization with pO2 increase and endothelial PTEN activation by inositol trispyrophosphate brings novel tumor treatment

Abstract

Tumor hypoxia is a characteristic of cancer cell growth and invasion, promoting angiogenesis, which facilitates metastasis. Oxygen delivery remains impaired because tumor vessels are anarchic and leaky, contributing to tumor cell dissemination. Counteracting hypoxia by normalizing tumor vessels in order to improve drug and radio therapy efficacy and avoid cancer stem-like cell selection is a highly challenging issue. We show here that inositol trispyrophosphate (ITPP) treatment stably increases oxygen tension and blood flow in melanoma and breast cancer syngeneic models. It suppresses hypoxia-inducible factors (HIFs) and proangiogenic/glycolysis genes and proteins cascade. It selectively activates the tumor suppressor phosphatase and tensin homolog (PTEN) in vitro and in vivo at the endothelial cell (EC) level thus inhibiting PI3K and reducing tumor AKT phosphorylation. These mechanisms normalize tumor vessels by EC reorganization, maturation, pericytes attraction, and lowering progenitor cells recruitment in the tumor. It strongly reduces vascular leakage, tumor growth, drug resistance, and metastasis. ITPP treatment avoids cancer stem-like cell selection, multidrug resistance (MDR) activation and efficiently enhances chemotherapeutic drugs activity. These data show that counteracting tumor hypoxia by stably restoring healthy vasculature is achieved by ITPP treatment, which opens new therapeutic options overcoming hypoxia-related limitations of antiangiogenesis-restricted therapies. By achieving long-term vessels normalization, ITPP should provide the adjuvant treatment required in order to overcome the subtle definition of therapeutic windows for in vivo treatments aimed by the current strategies against angiogenesis-dependent tumors.Electronic supplementary materialThe online version of this article (doi:10.1007/s00109-013-0992-6) contains supplementary material, which is available to authorized users.

ITPP Treatment of RG2 Glioblastoma in a Rat Model

“…ITPP had no effect on U87 cell proliferation in vitro. In another study by Kieda et al, it was described that ITPP treatment reduced the size of malignant melanomas in mice and reduced the metastatic invasion, leading to increased survival compared to control animals (2).…”

“…These vessels are permeable and allow tumour spreading. The driving force is thought to be the hypoxic state created by the tumour itself (2). It has been shown that inositol trispyrophosphate (ITPP) treatment increases oxygen delivery to the tumour and reduces tumour growth, thus resulting in a more favourable outcome in animal models with pancreatic cancer (3), liver cancer (4) and glioblastoma cells implanted on membranes (5).…”

“…It is called myo-inositol trispyrophosphate (ITPP) (9). ITPP increases the oxygen level and blood flow in experimental settings of melanoma and breast cancer models (2). ITPP also inhibited angiogenesis in chick chorioallantoic membrane (CAM) (5).…”

“…ITPP reduces HIF1α mRNA expression (2). HIF1α is associated with a higher number of vessels, tumour grade severity and treatment failure (2).…”

“…HIF1α is associated with a higher number of vessels, tumour grade severity and treatment failure (2). It has been suggested that hypoxic tumour cells are resistant to radiotherapy and chemotherapy through HIFs and it is thought that counteracting hypoxia in the tumour by normalizing tumour vessels could improve the results of the radiotherapy (2).…”