Margreet C.M. Vissers, PhD

Centre for Free Radical Research
Pathology Department
University of Otago, Christchurch, New Zealand

image of Dr. Margreet Vissers

Abstract: Rapid tumor growth initiates hypoxic stress and activates the transcription factor hypoxia-inducible factor (HIF)-1, promoting angiogenesis, glycolysis and enhanced resistance to radio- and chemotherapy. HIF-1 is down-regulated by oxygen-sensing hydroxylases that require vitamin C (ascorbate) as cofactor and we have observed an inverse correlation between cell ascorbate levels and HIF-1 activity. Our hypothesis is that poor vascular ascorbate delivery in a growing tumor limits cell ascorbate content and augments the hypoxic response, thereby driving tumor growth. Raising tumor ascorbate could reverse this effect. Our in vitro modelling of ascorbate uptake into tissues is consistent with this hypothesis and suggests that supra-physiological concentrations are required to saturate tumor tissue.

We have shown that HIF-1 is moderated by intracellular ascorbate in tumors grown in the Gulo-/- mouse, a model of human vitamin C dependency. Pre-clinical studies with tumor tissue from cancer patients have also shown a correlation between cellular ascorbate levels, HIF-1 activity, tumor size and patient outcome in breast, colorectal, endometrial and renal cancers. These results suggest that raising tumor ascorbate could slow tumor growth by moderating HIF-1 activation. Our data from tumor-bearing Gulo-/- mice suggests that achieving mM plasma ascorbate levels by daily administration of supra-physiological doses exerts an anti-tumor effect, with decreased HIF-1 and vascular endothelial growth factor protein expression as well as reduced microvessel density, tumor hypoxia and tumor growth. We have recently completed a pilot study with colorectal cancer patients who were given high dose vitamin C (1g/kg) for four days prior to surgical removal of the tumor. Our analysis of the tumor tissue indicates that a significant increase in ascorbate levels is achieved through the high dose intervention that could impact on HIF-1 activation. Together, our results support the suppression of HIF-1 as an anti-tumor activity of ascorbate that may be useful in a clinical setting.