Hypoxia-inducible factor-1 (HIF-1) is a heterodimer
transcription factor whose elevated activity in many
cancers helps them to survive under hypoxic conditions and enhances their capacity to grow invasively, establish
metastases, and survive chemo- or
radiotherapy. Optimal intracellular levels of ascorbate suppress the level and transcriptional activity of HIF-1under normoxic or mildly hypoxic conditions by supporting the activity of proly and asparagyl
hydroxylases that target HIF-1alpha. High intracellular ascorbate can also work in various ways to down-regulate activation of
NF-kappaB which, like HIF-1 is constitutively active in many
cancers and promotes aggressive behavior - in part by promoting transcription of HIF-1alpha. Yet recent evidence suggests that, even in the context of adequate ascorbate nutrition, the intracellular ascorbate content of many aggressive
cancers may be supoptimal for effective HIF-1 control. This likely reflects low expression or activity of the SVCT2 ascorbate transporter. The expression of SVCT2 in
cancers has so far received little study; but the extracellular acidity characteristic of many
tumors would be expected to reduce the activity of this transporter, which has a mildly alkaline pH optimum. Unfortunately, since SVCT2 has a high affinity for ascorbate, and its activity is nearly saturated at normal healthy serum levels of this
vitamin, increased
oral administration of ascorbate would be unlikely to have much impact on the intracellular ascorbate content of
tumors. However,
cancers in which HIF-1 is active express high levels of
glucose transporters such as GLUT-1, and these transporters can promote influx of
dehydroascorbic acid (DHA) via facilitated diffusion; once inside the cell, DHA is rapidly reduced to ascorbate, which effectively is "trapped" within the cell. Hence, episodic
intravenous infusions of modest doses of DHA may have potential for optimizing the intracellular ascorbate content of
cancers, potentially rendering them less aggressive. Indeed, several published studies have concluded that parenteral DHA--sometimes in quite modest doses--can retard the growth of transplanted
tumors in rodents. As an alternative or adjunctive strategy,
oral administration of
sodium bicarbonate, by normalizing the extracellular pH of
tumors, has the potential to boost the activity of SCTV2 in
tumor cells, thereby promoting increased ascorbate uptake. Indeed, the utility of oral
sodium bicarbonate for suppressing
metastasis formation in nude mice xenografted with a human
breast cancer has been reported. Hence, oral
sodium bicarbonate and intravenous DHA may have the potential to blunt the aggressiveness of certain
cancers in which suboptimal intracellular ascorbate levels contribute to elevated HIF-1 activity.