Department of Biology, Nazarbayev University, Astana 010000, Kazakhstan.
National Laboratory Astana, Nazarbayev University, Astana 010000, Kazakhstan.
Cells. 2022 Nov 1;11(21):3454. doi: 10.3390/cells11213454.
The turn-on mutations of the 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, -VC, because of its distinctive pharmacokinetics and lower toxicity. Thus, the -VC and ATO combination shows a promising path to treat KRAS-mutant cancers in clinical settings.
基因的激活突变，该基因编码一种与生长因子信号偶联的小分子 GTPase，导致近 25%的人类癌症，导致高度恶性肿瘤，预后不良。针对致癌 KRAS 仍然是肿瘤学中最具挑战性的任务。最近，已经开发出针对特定 G12C 突变 KRAS 的抑制剂，但由于它们产生了耐药性，因此临床效果有限。另一种方法是利用与葡萄糖依赖性氧化应激敏感性相关的 KRAS 突变癌细胞的代谢缺陷，成为一种有前途的间接癌症靶向方法。在这里，我们讨论了使用大剂量维生素 C (VC) 作为针对 KRAS 突变癌细胞的氧化“特洛伊木马”药物的用途，该药物可以与另一种氧化药物三氧化二砷 (ATO) 联合使用，以获得有效的选择性细胞毒性作用。此外，我们概述了 VC 的非天然对映异构体 -VC 的优势，因为它具有独特的药代动力学和更低的毒性。因此，-VC 和 ATO 的联合使用为治疗 KRAS 突变癌症提供了一种有前途的临床途径。
