The Vitamin C Enantiomers Possess a Comparable Potency in the Induction of Oxidative Stress in Cancer Cells but Differ in Their Toxicity

• Published in: International journal of molecular sciences Vol. 25; no. 5; p. 2531
• Main Authors: Begimbetova, Dinara, Burska, Agata N, Baltabekova, Aidana, Kussainova, Assiya, Kukanova, Assiya, Fazyl, Fatima, Ibragimova, Milana, Manekenova, Kenzhekyz, Makishev, Abay, Bersimbaev, Rakhmetkazhi I, Sarbassov, Dos D
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 22.02.2024; MDPI
• Subjects: Animals; Arsenic Trioxide - pharmacology; Ascorbic Acid - pharmacology; Cancer; Cancer cells; Cancer therapies; Cell growth; Cytotoxicity; D-Isoascorbic acid (D-VC); Enantiomers; Glucose; Growth factors; Kinases; L-ascorbic acid (L-VC); Mice; Mitochondria; Mutation; Neoplasms; Oxidation; Oxidative Stress; Phosphorylation; Proto-Oncogene Proteins p21(ras); reactive oxidative species (ROS); Toxicity; Tumorigenesis; Venture capital; Vitamin C; vitamin C (VC) or ascorbic acid; Vitamins; Vitamins - pharmacology; Kazakhstan; toxicity; D-Isoascorbic acid (D-VC); reactive oxidative species (ROS); L-ascorbic acid (L-VC); vitamin C (VC) or ascorbic acid
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25052531

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 Kras -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.