N′1,n′3-dimethyl-n′1,n′3-bis(Phenylcarbonothioyl) propanedihydrazide (elesclomol) selectively kills cisplatin resistant lung cancer cells through reactive oxygen species (ros)

Medhi Wangpaichitr, Chunjing Wu, Min You, Johnathan C. Maher, Vy Thuy Dinh, Lynn G. Feun, Niramol Savaraj

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

Cisplatin is an important chemotherapeutic agent in lung cancer treatment. The mechanism of drug resistance to cisplatin is complex and historically has been difficult to overcome. We report here that cisplatin resistant lung cancer cell lines possess high basal levels of reactive oxygen species (ROS) when compared to normal cells and their parental cell counterparts. These resistant cells also have low thioredoxin (TRX) levels which may be one of the contributory factors to high ROS. N′1,N′3-dimethyl-N′1,N′3-bis(phenylcarbonothioyl) propanedihydrazide (elesclomol), an agent known to increase ROS is selectively toxic to cisplatin-resistant cells, while sparing normal cells and the parental counterpart. The cytotoxic effect of elesclomol in resistant cells is accompanied by further decreases in TRX and glutathione (GSH) antioxidant systems, while opposite results were found in parental cells. The ID50 of elesclomol in cisplatin-resistant cells ranged from 5–10 nM, which is well within clinically achievable ranges. N-Acetylcysteine (NAC), which is known to neutralize ROS, can abolish the cytotoxic effect of elesclomol, suggesting that the cytotoxic effect results from increased ROS. Overall, our data suggest that elesclomol selectively kills cisplatin-resistant tumor cells through increased ROS. This agent may hold potential to overcome cisplatin resistance and should be further explored to treat patients who have failed cisplatin therapy.

Original languageEnglish (US)
Pages (from-to)23-38
Number of pages16
JournalCancers
Volume1
Issue number1
DOIs
StatePublished - Dec 2009

Keywords

  • Cisplatin
  • Drug resistant
  • Elesclomol
  • Lung cancer
  • ROS

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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