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.
Highlights
Cisplatin resistance often involves multiple mechanisms including drug transport, inactivation of drug, and cell type dependent DNA repair, making resistance to cisplatin difficult to overcome.One of the known pharmacologic actions of cisplatin is disruption of the redox system through inhibition of thioredoxin reductase (TrxR) [1,2]
We have studied two pairs of small cell lung cancer (SCLC), two pairs of non small cell lung cancer (NSCLC) and their cisplatin resistant counterparts as well as normal fibroblast cell line, BJ-1
Our results showed that reactive oxygen species (ROS) is increased in all cisplatin resistant cell lines when compared to their parental counterpart cells
Summary
Cisplatin resistance often involves multiple mechanisms including drug transport, inactivation of drug, and cell type dependent DNA repair, making resistance to cisplatin difficult to overcome. One of the known pharmacologic actions of cisplatin is disruption of the redox system through inhibition of thioredoxin reductase (TrxR) [1,2]. Inhibition of TRX by cisplatin leads to increased ROS resulting in further damage of DNA and subsequent cell death [4,5]. We have found that cisplatin resistant cell lines harbor high basal levels of ROS which could be exploited as a therapeutic target. N′1,N′3-dimethyl-N′1,N′3-bis(phenylcarbonothioyl)propanedihydrazide (elesclomol) is a novel agent derived from a phenotypic screen for small molecules with potent proapoptotic activity through the induction of oxidative stress [6]. Treatment with elesclomol results in rapid generation of ROS and the induction of genes transcription that are responsible for oxidative stress [6]. We evaluate the antitumor effect of this agent in a panel of small cell lung cancer (SCLC) and non small cell lung cancer (NSCLC) cisplatin resistant cell lines
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