Abstract:
The use of vitamin C (VC) in high doses demonstrates a potent tumor suppressive effect by
mediating a glucose-dependent oxidative stress in Kirsten rat sarcoma (KRAS) mutant cancer cells.
VC with arsenic trioxide (ATO) is a promising drug combination that might lead to the development
of effective cancer therapeutics. Considering that a tumor suppressive effect of VC requires its highdose administration, it is of interest to examine the toxicity of two enantiomers of VC (enantiomer
d-optical isomer D-VC and natural l-optical isomer L-VC) in vitro and in vivo. We show that the
combinations of L-VC with ATO and D-VC with ATO induced a similar cytotoxic oxidative stress in
KrasG12D-expressing mutant cancer cells as indicated by a substantial increase in reactive oxidative
species (ROS) production and depolarization of mitochondria. To examine the L-VC and D-VC
toxicity effects, we administered high doses of D-VC and L-VC to CD1 mice and carried out an
evaluation of their toxic effects. The daily injections of L-VC at a dose of 9.2 g/kg for 18 days were
lethal to mice, while 80% of mice remained alive following the similar high-dose administration of
D-VC. Following the drug injection courses and histopathological studies, we determined that a
natural form of VC (L-VC) is more harmful and toxic to mice when compared to the effects caused by
the similar doses of D-VC. Thus, our study indicates that the two enantiomers of VC have a similar
potency in the induction of oxidative stress in cancer cells, but D-VC has a distinctive lower toxicity
in mice compared to L-VC. While the mechanism of a distinctive toxicity between D-VC and L-VC
is yet to be defined, our finding marks D-VC as a more preferable option compared to its natural
enantiomer L-VC in clinical settings.
