Enhancing an Oxidative "Trojan Horse" Action of Vitamin C with Arsenic Trioxide for Effective Suppression of KRAS-Mutant Cancers: A Promising Path at the Bedside.

The turn-on mutations of the KRAS gene, coding a small GTPase coupling growth factor signaling, are contributing to nearly 25% of all human cancers, leading to highly malignant tumors with poor outcomes. Targeting of oncogenic KRAS remains a most challenging task in oncology. Recently, the specific G12C mutant KRAS inhibitors have been developed but with a limited clinical outcome because they acquire drug resistance. Alternatively, exploiting a metabolic breach of KRAS-mutant cancer cells related to a glucose-dependent sensitivity to oxidative stress is becoming a promising indirect cancer targeting approach. Here, we discuss the use of a vitamin C (VC) acting in high dose as an oxidative "Trojan horse" agent for KRAS-mutant cancer cells that can be potentiated with another oxidizing drug arsenic trioxide (ATO) to obtain a potent and selective cytotoxic impact. Moreover, we outline the advantages of VC's non-natural enantiomer, D-VC, because of its distinctive pharmacokinetics and lower toxicity. Thus, the D-VC and ATO combination shows a promising path to treat KRAS-mutant cancers in clinical settings.

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.

A carbon dot-based Co-nanozyme with alkaline phosphatase - mechanism and application.

Elevated levels of alkaline phosphatase (ALP) are associated with bone metastasis, liver cancer, prostate cancer, breast cancer, and many other diseases or stem cell marker. It is therefore of great significance to quantitatively detect the ALP levels by a rapid, highly sensitive, and easy-to-use strip paper test. In the present work, we discovered an enhancement of ALP activity upon the addition of cauliflower-derived carbon dots (CFCDs), which can be applied as a sensor for ALP. The mixed ALP and CFCDs exhibited a typical Michaelis Menten mechanism with increased V max and reduced K m compared to ALP alone. High-Resolution Atomic Force Microscopy (HR-AFM) reveals the dimensions of ALP, the CFCDs, and the phosphatase substrate para-nitrophenyl phosphate (pNPP), as well as the potential interactions among them. The role of the CFCDs was identified as the addition of reaction centers to ALP; in other words, a competitive activator. Besides the improved kinetics, the yield of dephosphorylated product was also increased by at least twice upon the addition of CFCDs. Taking advantage of this effect, a portable CFCD-based paper strip assay was developed to achieve sensitive detection of abnormally elevated ALP levels and visualization of cancer stem cells or proteins by phosphatase-conjugated antibodies. Our findings show great promise for disease diagnosis and bioassays related to ALP enhancement that may be used for protein or cell detection.