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Conference Paper: Arsenic trioxide-induced cytotoxicity in small cell lung cancer via altered redox homeostasis and mitochondrial integrity

TitleArsenic trioxide-induced cytotoxicity in small cell lung cancer via altered redox homeostasis and mitochondrial integrity
Authors
Issue Date2014
Citation
The 21st Hong Kong International Cancer Congress (HKICC 2014), Hong Kong, 21 November 2014. How to Cite?
AbstractArsenic trioxide (ATO) has demonstrated anticancer activity in different malignancies, especially acute promyelocytic leukemia, with a wide array of putative mechanisms. In this study, we aimed to elucidate the activity and mechanisms of ATO in small cell lung cancer (SCLC). A panel of SCLC cell lines (H841, DMS79, H526, H69 and H187) was employed to demonstrate the activity of ATO. Cell viability, apoptosis and mitochondrial membrane depolarization were assessed. Western blotting was performed to determine the alteration of pro-apoptotic and anti-apoptotic mediators. Reactive oxygen species (ROS) (hydrogen peroxide and superoxide) and intracellular glutathione (GSH) were measured. Antioxidants, N-acetyl-L-cysteine (NAC) and butylated hydroxyanisole (BHA), were applied to restore GSH content and reduce production of ROS. All SCLC cell lines were relatively sensitive to ATO with IC50 values below 10 μM. ATO induced cell death mainly through apoptosis in H841 cells in a dose-dependent manner. Hydrogen peroxide was the major ROS in SCLC cells induced by ATO. Along with GSH depletion and Bcl-2 downregulation, mitochondrial membrane permeabilization was enhanced, followed by release of AIF and SMAC from mitochondria to initiate different cell death pathways. NAC reversed cell death and molecular changes induced by ATO via restoring GSH and reducing ROS content. BHA inhibited hydrogen peroxide production completely and partially restored GSH content accounting for partial reversal of cell inhibition and mitochondrial dysfunction. Nonetheless, ATO reduced both reduced and oxidized form of thioredoxin 1 (Trx1) with no effect on Trx1 redox potential. ATO led to cell death in SCLC mainly through mitochondrial dysfunction, resulting from altered cellular redox homeostasis, namely, hydrogen peroxide generation, GSH depletion and Trx1 downregulation.
DescriptionCongress Theme: Translating Discoveries into Prevention and Cures
Persistent Identifierhttp://hdl.handle.net/10722/206850

 

DC FieldValueLanguage
dc.contributor.authorZheng, Cen_US
dc.contributor.authorLam, SKen_US
dc.contributor.authorLi, Yen_US
dc.contributor.authorLeung, LLen_US
dc.contributor.authorHo, JCMen_US
dc.date.accessioned2014-12-02T10:28:33Z-
dc.date.available2014-12-02T10:28:33Z-
dc.date.issued2014en_US
dc.identifier.citationThe 21st Hong Kong International Cancer Congress (HKICC 2014), Hong Kong, 21 November 2014.en_US
dc.identifier.urihttp://hdl.handle.net/10722/206850-
dc.descriptionCongress Theme: Translating Discoveries into Prevention and Curesen_US
dc.description.abstractArsenic trioxide (ATO) has demonstrated anticancer activity in different malignancies, especially acute promyelocytic leukemia, with a wide array of putative mechanisms. In this study, we aimed to elucidate the activity and mechanisms of ATO in small cell lung cancer (SCLC). A panel of SCLC cell lines (H841, DMS79, H526, H69 and H187) was employed to demonstrate the activity of ATO. Cell viability, apoptosis and mitochondrial membrane depolarization were assessed. Western blotting was performed to determine the alteration of pro-apoptotic and anti-apoptotic mediators. Reactive oxygen species (ROS) (hydrogen peroxide and superoxide) and intracellular glutathione (GSH) were measured. Antioxidants, N-acetyl-L-cysteine (NAC) and butylated hydroxyanisole (BHA), were applied to restore GSH content and reduce production of ROS. All SCLC cell lines were relatively sensitive to ATO with IC50 values below 10 μM. ATO induced cell death mainly through apoptosis in H841 cells in a dose-dependent manner. Hydrogen peroxide was the major ROS in SCLC cells induced by ATO. Along with GSH depletion and Bcl-2 downregulation, mitochondrial membrane permeabilization was enhanced, followed by release of AIF and SMAC from mitochondria to initiate different cell death pathways. NAC reversed cell death and molecular changes induced by ATO via restoring GSH and reducing ROS content. BHA inhibited hydrogen peroxide production completely and partially restored GSH content accounting for partial reversal of cell inhibition and mitochondrial dysfunction. Nonetheless, ATO reduced both reduced and oxidized form of thioredoxin 1 (Trx1) with no effect on Trx1 redox potential. ATO led to cell death in SCLC mainly through mitochondrial dysfunction, resulting from altered cellular redox homeostasis, namely, hydrogen peroxide generation, GSH depletion and Trx1 downregulation.en_US
dc.languageengen_US
dc.relation.ispartof21st HKICC 2014en_US
dc.titleArsenic trioxide-induced cytotoxicity in small cell lung cancer via altered redox homeostasis and mitochondrial integrityen_US
dc.typeConference_Paperen_US
dc.identifier.emailLam, SK: sklam77@hku.hken_US
dc.identifier.emailHo, JCM: jhocm@hku.hken_US
dc.identifier.authorityHo, JCM=rp00258en_US
dc.identifier.hkuros241621en_US

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