Oncotarget

Research Papers:

Exploiting ROS and metabolic differences to kill cisplatin resistant lung cancer

Medhi Wangpaichitr, Chunjing Wu, Ying Ying Li, Dan J.M. Nguyen, Hande Kandemir, Sumedh Shah, Shumei Chen, Lynn G. Feun, Jeffrey S. Prince, Macus T. Kuo and Niramol Savaraj _

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Oncotarget. 2017; 8:49275-49292. https://doi.org/10.18632/oncotarget.17568

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Abstract

Medhi Wangpaichitr1,2, Chunjing Wu1, Ying Ying Li3, Dan J.M. Nguyen4, Hande Kandemir5, Sumedh Shah4, Shumei Chen6, Lynn G. Feun3, Jeffrey S. Prince4, Macus T. Kuo7 and Niramol Savaraj1,3

1Miami VA Healthcare System, Research Service, Miami, FL, USA

2Department of Surgery, Cardiothoracic Surgery, University of Miami, Miami, FL, USA

3Department of Medicine, Hematology/Oncology, University of Miami, Miami, FL, USA

4Department of Biology, University of Miami, Miami, FL, USA

5School of Medicine, Koc University, Istanbul, Turkey

6Department of Neurosurgery, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan

7Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

Correspondence to:

Medhi Wangpaichitr, email: mwangpaichitr@med.miami.edu

Keywords: lung cancer, reactive oxygen species, oxidative metabolism, riluzole, resistance

Received: January 30, 2017     Accepted: April 17, 2017     Published: May 02, 2017

ABSTRACT

Cisplatin resistance remains a major problem in the treatment of lung cancer. We have discovered that cisplatin resistant (CR) lung cancer cells, regardless of the signaling pathway status, share the common parameter which is an increase in reactive oxygen species (ROS) and undergo metabolic reprogramming. CR cells were no longer addicted to the glycolytic pathway, but rather relied on oxidative metabolism. They took up twice as much glutamine and were highly sensitive to glutamine deprivation. Glutamine is hydrolyzed to glutamate for glutathione synthesis, an essential factor to abrogate high ROS via xCT antiporter. Thus, blocking glutamate flux using riluzole (an amyotropic lateral sclerosis approved drug) can selectively kill CR cells in vitro and in vivo. However, we discovered here that glutathione suppression is not the primary pathway in eradicating the CR cells. Riluzole can lead to further decrease in NAD+ (nicotinamide adenine dinucleotide) and lactate dehydrogenase-A (LDHA) expressions which in turn further heightened oxidative stress in CR cells. LDHA knocked-down cells became hypersensitive to riluzole treatments and possessed increased levels of ROS. Addition of NAD+ re-stabilized LDHA and reversed riluzole induced cell death. Thus far, no drugs are available which could overcome cisplatin resistance or kill cisplatin resistant cells. CR cells possess high levels of ROS and undergo metabolic reprogramming. These metabolic adaptations can be exploited and targeted by riluzole. Riluzole may serve as a dual-targeting agent by suppression LDHA and blocking xCT antiporter. Repurposing of riluzole should be considered for future treatment of cisplatin resistant lung cancer patients.


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