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Combination of arsenic trioxide and chemotherapy in small cell lung cancer.
- Source :
-
Lung cancer (Amsterdam, Netherlands) [Lung Cancer] 2013 Nov; Vol. 82 (2), pp. 222-30. Date of Electronic Publication: 2013 Sep 03. - Publication Year :
- 2013
-
Abstract
- Introduction: Small cell lung cancer (SCLC) carries high mortality despite standard chemotherapy. Arsenic trioxide (ATO) has demonstrated clinical efficacy in leukemia and in vitro activity in various solid tumors. This study was conducted to determine the in vitro and in vivo combination effects of ATO and chemotherapy in SCLC.<br />Materials and Methods: The in vitro model consisted of 5 SCLC cell lines (H187, H526, H69, H841 and DMS79) and the anti-proliferative effects of ATO, cisplatin, etoposide or combinations thereof were measured. Synergism was determined by calculation of the combination index (CI) according to Chou and Talalay. Assays for apoptosis, intracellular glutathione (GSH) content, and mitochondrial membrane depolarization (MMD) were performed. Arsenic content was measured by inductively coupled plasma-mass spectrometry. Expression level of MRP1, MRP2 and pH2AX was detected by Western blot while cellular pH2AX level was monitored by immunofluorescent staining. An in vivo xenograft model in nude mice was established with a H841 cell line to test the effects of drug combinations.<br />Results: All 5 SCLC cell lines were sensitive to ATO, with IC(50) values (48 h) 1.6-8 μM. Synergistic or additive effects were obtained by combining cisplatin with ATO in all 5 cell lines. Combination of etoposide with ATO resulted in antagonistic or barely additive effects. Apoptotic assays and pH2AX immunofluorescent staining corroborated the synergistic combination of ATO and cisplatin. In addition, the ATO/cisplatin combination enhanced MMD, depleted GSH, downregulated MRP2 and elevated intracellular ATO content compared with either ATO or cisplatin alone. In vivo combination of ATO and cisplatin also demonstrated synergism in the H841 xenograft model.<br />Conclusions: There was clinically relevant in vitro activity of ATO in a panel of 5 SCLC cell lines. Significant synergism was demonstrated with the ATO/cisplatin combination, while antagonism was noted with the ATO/etoposide combination in both in vitro and in vivo models.<br /> (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)
- Subjects :
- Animals
Antineoplastic Agents administration & dosage
Antineoplastic Agents toxicity
Apoptosis drug effects
Arsenic Trioxide
Arsenicals administration & dosage
Cell Line, Tumor
Cell Proliferation drug effects
Cisplatin pharmacology
Cisplatin toxicity
DNA Damage
Disease Models, Animal
Drug Synergism
Etoposide pharmacology
Etoposide toxicity
Female
Glutathione metabolism
Humans
Lung Neoplasms drug therapy
Membrane Potential, Mitochondrial drug effects
Mice
Multidrug Resistance-Associated Protein 2
Multidrug Resistance-Associated Proteins metabolism
Oxides administration & dosage
Oxides toxicity
Reactive Oxygen Species metabolism
Small Cell Lung Carcinoma drug therapy
Xenograft Model Antitumor Assays
Antineoplastic Agents pharmacology
Arsenicals pharmacology
Lung Neoplasms metabolism
Lung Neoplasms pathology
Oxides pharmacology
Small Cell Lung Carcinoma metabolism
Small Cell Lung Carcinoma pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1872-8332
- Volume :
- 82
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Lung cancer (Amsterdam, Netherlands)
- Publication Type :
- Academic Journal
- Accession number :
- 24041618
- Full Text :
- https://doi.org/10.1016/j.lungcan.2013.08.022