ARSENIC TRIOXIDE AND D-VITAMIN C DRUG COMBINATION INDUCES OXIDATIVE STRESS AND ALTERS ELECTRON TRANSPORT CHAIN ACTIVITY OF KRAS-MUTANT CANCER CELLS

Abstract

Mutation in Kirsten rat sarcoma (KRAS) protooncogene is implicated in about 25-30% of all human cancers. It is usually associated with aggressive tumor progression and poor prognosis. Until now targeting KRAS-mutant cancer remains quite challenging even though several approaches were applied. However, all such strategies led to drug resistance which makes it even more challenging to specifically target KRAS-mutant cancer. Arsenic trioxide and D-Vitamin C (ATO/D-VC) is a novel approach to targeting KRAS-mutant cancer cells using vulnerabilities in their metabolism. These cells are highly sensitive to oxidative imbalance which makes them a perfect target for ATO/D-VC drug combination as it can trigger so-called suicidal reactive oxygen species production by mitochondria (SPRM). In the current study the molecular aspects of ATO/D-VC mechanism of action was explored. It was shown that downregulation of succinate dehydrogenase (complex II) of the electron transport chain might be the primary cause of SPRM triggered by the action of ATO/D-VC synergetic drug combination. Understanding the mechanism behind SRPM is essential for comprehending the potent cytotoxicity against KRAS-mutant cancers. ATO/D-VC oxidative drug combination showed effectiveness during Phase 1 and currently undergoes Phase 2 of clinical trials in Kazakhstan.