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Int J Cancer. 2019 Aug 31. doi: 10.1002/ijc.32658. [Epub ahead of print]

A Chirality-Dependent Action of Vitamin C in Suppressing KRAS Mutant Tumor Growth by the Oxidative Combination: Rationale for Cancer Therapeutics.

Author information

1
Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
2
The University of Texas Graduate School of Biomedical Sciences at Houston, Texas, USA.
3
Department of Surgery, University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
4
Department of Biostatistics, University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
5
Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
6
Department of Natural Sciences, The L.N. Gumilyov Eurasian National University, Nur-Sultan, Kazakhstan.
7
Department of Biology, Nazarbayev University, Nur-Sultan, Kazakhstan.

Abstract

Kirsten rat sarcoma (KRAS) mutant cancers, which constitute the vast majority of pancreatic tumors, are characterized by their resistance to established therapies and high mortality rates. Here, we developed a novel and extremely effective combinational therapeutic approach to target KRAS mutant tumors through the generation of a cytotoxic oxidative stress. At high concentrations, Vitamin C (VC) is known to provoke oxidative stress and selectively kill KRAS mutant cancer cells, although its effects are limited when it is given as monotherapy. We found that the combination of VC and the oxidizing drug arsenic trioxide (ATO) is an effective therapeutic treatment modality. Remarkably, its efficiency is dependent on chirality of VC as its enantiomer D-VC is significantly more potent than the natural L-VC. Thus, our results demonstrate that the oxidizing combination of arsenic trioxide and D-VC is a promising approach for the treatment of KRAS mutant human cancers. This article is protected by copyright. All rights reserved.

KEYWORDS:

Kirsten rat sarcoma (KRAS) mutant cancer cells; apoptosis; drug combination; oxidative stress; reactive oxygen species (ROS)

PMID:
31472018
DOI:
10.1002/ijc.32658

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