Human tumors may contain high concentrations of ascorbic acid, but little i
s known about how they acquire the vitamin. Certain specialized cells can t
ransport ascorbic acid directly through a sodium ascorbate cotransporter, b
ut in most cells, vitamin C enters through the facilitative glucose transpo
rters (GLUTs) in the form of dehydroascorbic acid, which is then reduced in
tracellularly and retained as ascorbic acid. Mice with established hematopo
ietic and epithelial cell xenografts were studied for the accumulation of i
njected ascorbic acid and dehydroascorbic acid. Most hematopoietic and epit
helial tumor cell lines can only transport vitamin C in the oxidized form (
dehydroascorbic acid) in vitro; however, when grown as xenografts in mice,
they rapidly accumulated vitamin C after administration of radiolabeled asc
orbic acid, The involvement of the GLUTs in vitamin C uptake by the xenogra
fted tumors was demonstrated by competitive inhibition with D-glucose but n
ot L-glucose, Because the malignant cells were not capable of directly tran
sporting ascorbic acid, we reasoned that the ascorbic acid was oxidized to
dehydroascorbic acid in the tumor microenvironment. Tumor accumulation of v
itamin C in animals injected,vith ascorbic acid was inhibited by coadminist
ration of superoxide dismutase, implying a role for superoxide anion in the
oxidation of ascorbic acid. Whereas the epithelial cancer cell lines could
not generate superoxide anion in culture, the minced xenograft tumors did.
Our studies show the transport of dehydroascorbic acid by GLUTs is a means
by which tumors acquire vitamin C and indicate the oxidation of ascorbic a
cid by superoxide anion produced by cells in the tumor stroma as a mechanis
m for generating the transportable form of the vitamin.