ArticleJournal of experimental & clinical cancer research : CR2010
Adaphostin toxicity in a sensitive non-small cell lung cancer model is mediated through Nrf2 signaling and heme oxygenase 1.
Article in Journal of experimental & clinical cancer research : CR, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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8 citing papers in PubMed, 17 citations in OpenAlex.
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- Combinatorial effects of histone deacetylase inhibitors (HDACi), vorinostat and entinostat, and adaphostin are characterized by distinct redox alterations.Cancer chemotherapy and pharmacology · 2018Article
- Role of Nrf2/ARE pathway in protective effect of electroacupuncture against endotoxic shock-induced acute lung injury in rabbits.PloS one · 2014Article
- Perspective: Opportunities in recalcitrant, rare and neglected tumors.Oncology reports · 2013Article
- The lipophilic bullet hits the targets: medicinal chemistry of adamantane derivatives.Chemical reviews · 2013Review
- Redox control of leukemia: from molecular mechanisms to therapeutic opportunities.Antioxidants & redox signaling · 2013Review
- ON 01910.Na is selectively cytotoxic for chronic lymphocytic leukemia cells through a dual mechanism of action involving PI3K/AKT inhibition and induction of oxidative stress.Clinical cancer research : an official journal of the American Association for Cancer Research · 2012Article
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3 authors at 1 institution in 1 country.
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Abstract
backgroundPreclinical toxicity of adaphostin has been related to oxidative stress. This study investigated the regulatory mechanism underlying adaphostin induction of heme oxygenase 1 (HMOX1) which plays a significant role in modulation of drug-induced toxicity in the non-small cell lung cancer cell line model, NCI-H522.
methodsThe transcriptional response of NCI-H522 to adaphostin prominently involved oxidative stress genes, particularly HMOX1. Reactive oxygen species (ROS) involvement was additionally established by generation of ROS prior to modulation of adaphostin-toxicity with antioxidants. To identify up-stream regulatory elements of HMOX1, immunofluorescence was used to evaluate nuclear translocation of the transcription factor, NF-E2-related factor 2 (Nrf2), in the presence of adaphostin. The PI3-kinase inhibitor, wortmannin, was employed as a pharmacological inhibitor of this process.
resultsGeneration of ROS provided a substantial foundation for the sensitivity of NCI-H522 to adaphostin. However, in contrast to leukemia cell lines, transcriptional response to oxidative stress was associated with induction of HMOX1, which was dependent on nuclear translocation of the transcription factor, Nrf2. Pretreatment of cells with wortmannin inhibited translocation of Nrf2 and induction of HMOX1. Wortmannin pretreatment was also able to diminish adaphostin induction of HMOX1, and as a consequence, enhance the toxicity of adaphostin to NCI-H522.
conclusionsAdaphostin-induced oxidative stress in NCI-H522 was mediated through nuclear translocation of Nrf2 leading to upregulation of HMOX1. Inhibition of Nrf2 translocation by wortmannin inhibited this cytoprotective response, and enhanced the toxicity of adaphostin, suggesting that inhibitors of the PI3K pathway, such as wortmannin, might augment the antiproliferative effects of adaphostin in solid tumors that depend on the Nrf2/ARE pathway for protection against oxidative stress.
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