Targeting the kynurenine pathway for the treatment of cisplatin-resistant lung cancer

Dan J.M. Nguyen, George Theodoropoulos, Ying Ying Li, Chunjing Wu, Wei Sha, Lynn G. Feun, Theodore J. Lampidis, Niramol Savaraj, Medhi Wangpaichitr

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Cisplatin resistance is a major barrier in the effective treatment of lung cancer. Cisplatin-resistant (CR) lung cancer cells do not primarily use glucose but rather consume amino acids such as glutamine and tryptophan (Trp) for survival. CR cells activate the kynurenine (KYN) pathway (KP) to cope with excessive reactive oxygen species (ROS) and maintain homeostasis for growth and proliferation. Consequently, indoleamine 2,3-dioxygenase-1 (IDO1) becomes an essential enzyme for CR cells' survival because it initiates and regulates the first step in the KP. Increased IDO1 activities and ROS levels are found in CR cells versus cisplatin-sensitive lung cancer. Importantly, significantly greater KYN/Trp ratio (P = 0.005) is detected in serum of patients who fail cisplatin when compared with naive treatment. Knocking down IDO1 using shRNA or IDO1 inhibitors heightens ROS levels and results in a significant growth inhibitory effect only on CR cells and not on cisplatin-sensitive cells. Exposing CR cells to antioxidant (TIRON) results in suppression of IDO1 activity and confers resistance to IDO1 inhibition, indicating an interrelationship between ROS and IDO1. Because KYN plays a critical role in reprogramming naive T cells to the immune-suppressive regulatory T-cell (T-reg) phenotype, we observed higher expression of TGFb, FoxP3, and CD4+CD25+ in mice bearing CR tumors compared with tumors from cisplatin-sensitive counterparts.

Original languageEnglish (US)
Pages (from-to)105-117
Number of pages13
JournalMolecular Cancer Research
Volume18
Issue number1
DOIs
StatePublished - Jan 1 2020

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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