The Vitamin C Enantiomers Possess a Comparable Potency in the Induction of Oxidative Stress in Cancer Cells but Differ in Their Toxicity
Begimbetova D. Burska A.N. Baltabekova A. Kussainova A. Kukanova A. Fazyl F. Ibragimova M. Manekenova K. Makishev A. Bersimbaev R.I. Sarbassov D.D.
March 2024Multidisciplinary Digital Publishing Institute (MDPI)
International Journal of Molecular Sciences
2024#25Issue 5
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 high-dose 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.
D-Isoascorbic acid (D-VC) , L-ascorbic acid (L-VC) , reactive oxidative species (ROS) , toxicity , vitamin C (VC) or ascorbic acid
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National Laboratory Astana, Nazarbayev University, Astana, 010000, Kazakhstan
School of Medicine, Nazarbayev University, Astana, 010000, Kazakhstan
Department of Experimental Medicine, University of Genoa, Genoa, 16132, Italy
Department of General Biology and Genomics, Institute of Cell Biology and Biotechnology, L.N. Gumilyov Eurasian National University, Astana, 010008, Kazakhstan
Department of Oncology, Astana Medical University, Astana, 010000, Kazakhstan
Department of Pathological Anatomy, Astana Medical University, Astana, 010000, Kazakhstan
Department of Biology, School of Sciences and Humanities, Nazarbayev University, Astana, 010000, Kazakhstan
National Laboratory Astana
School of Medicine
Department of Experimental Medicine
Department of General Biology and Genomics
Department of Oncology
Department of Pathological Anatomy
Department of Biology
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