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

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.

Molecular and immunological changes in blood of rats exposed to various doses of asbestos dust.

BACKGROUND: Asbestos-related diseases are a group of diseases resulting from the inhalation of asbestos fibres and their subsequent deposition in the lung parenchyma, which causes the development of inflammatory and fibrotic processes in the respiratory system. Cases of the disease often occur in the practice of doctors. AIMS: The purpose of the study was to examine the level of circulating-free mitochondrial DNA (cf mtDNA), pro-inflammatory cytokines, immunological status and structural changes in the lung of rats exposed to various doses of asbestos dust. METHODS: Immune monitoring was performed using the peripheral blood samples of 40 male Wistar rats exposed and unexposed to asbestos dust. cf mtDNA copy numbers were detected using quantitative real-time polymerase chain reaction (qRT-PCR) and cytokines were determined using a rat Enzyme Linked Immuno Sorbent Assay (ELISA) kit. RESULTS: A comprehensive assessment of the histopathological study performed under exposure to asbestos at a dose of 25 mg and 50 mg showed the presence of pronounced structural defects in the lung tissue of laboratory rats. The level of cf mtDNA in plasma of rats exposed to asbestos at a dose of 25 mg was reliably higher than that of control rats, and animals exposed to asbestos at a dose of 50 mg. The highest levels of pro-inflammatory cytokines IL-6 and TNF-a were also observed after asbestos dusting at a dose of 25 mg. CONCLUSIONS: According to the results of the immunological status obtained, the decrease in the levels of pro-inflammatory cytokines in the blood plasma at 50 mg is due to the immunosuppressive effect in the rat immune system at this dose. A positive correlation was found between TNF-a level and copy numbers of cf mtDNA at a dose of 25 mg.

The Oxidative Drug Combination for Suppressing KRAS G12D Inducible Tumour Growth.

Background: Kirsten rat sarcoma (KRAS) protein is an essential contributor to the development of pancreatic ductal adenocarcinoma (PDAC). KRAS G12D and G12V mutant tumours are significant challenges in cancer therapy due to high resistance to the treatment. Objective: To determine how effective is the ATO/D-VC combination in suppression of PDAC the mouse transgenic model. This study investigated the antitumour effect of a novel combination of arsenic trioxide (ATO) and D-ascorbic acid isomer (D-VC). Such a combination can be used to treat KRAS mutant cancer by inducing catastrophic oxidative stress. Methods: In this study, we examined the effectiveness of ATO and D-VC on xenograft models-AK192 cells transplanted into mice. Previously, it has been shown that a high concentration of Vitamin C (VC) selectively can kill the cells expressing KRAS. Results: The results of this study demonstrated that the combination of VC with a low dose of the oxidizing drug ATO led to the enhancement of the therapeutic effect. These findings suggest that the combined treatment using ATO and D-VC is a promising approach to overcome the limitation of drug selectivity and efficacy.