TY - JOUR
T1 - Enhancing an Oxidative "Trojan Horse" Action of Vitamin C with Arsenic Trioxide for Effective Suppression of KRAS-Mutant Cancers
T2 - A Promising Path at the Bedside
AU - Burska, Agata N
AU - Ilyassova, Bayansulu
AU - Dildabek, Aruzhan
AU - Khamijan, Medina
AU - Begimbetova, Dinara
AU - Molnár, Ferdinand
AU - Sarbassov, Dos D
PY - 2022/11/1
Y1 - 2022/11/1
N2 - 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.
AB - 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.
KW - Humans
KW - Arsenic Trioxide/pharmacology
KW - Ascorbic Acid/pharmacology
KW - Proto-Oncogene Proteins p21(ras)/genetics
KW - Reactive Oxygen Species/metabolism
KW - Cell Line, Tumor
KW - Oxidative Stress
KW - Vitamins/pharmacology
KW - Oxidation-Reduction
KW - Neoplasms/drug therapy
U2 - 10.3390/cells11213454
DO - 10.3390/cells11213454
M3 - Review article
C2 - 36359850
SN - 2073-4409
VL - 11
JO - Cells
JF - Cells
IS - 21
ER -