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
Burska A.N. Ilyassova B. Dildabek A. Khamijan M. Begimbetova D. Molnár F. Sarbassov D.D.
November 2022MDPI
Cells
2022#11Issue 21
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.
arsenic trioxide (ATO) , Kirsten rat sarcoma (KRAS) mutant ancers , oxidative stress , reactive oxygen species (ROS) , suicidal ROS production by mitochondrial (SRPM) , vitamin C (VC also known as ascorbic acid) , Warburg effect
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Department of Biology, Nazarbayev University, Astana, 010000, Kazakhstan
National Laboratory Astana, Nazarbayev University, Astana, 010000, Kazakhstan
Department of Biology
National Laboratory Astana
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