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Pemetrexed induces apoptosis in malignant mesothelioma and lung cancer cells through activation of reactive oxygen species and inhibition of sirtuin 1
- Source :
- Oncology Reports. 33:2411-2419
- Publication Year :
- 2015
- Publisher :
- Spandidos Publications, 2015.
-
Abstract
- Pemetrexed is a multitargeted antifolate used for the treatment of malignant mesothelioma and non-small cell lung cancer (NSCLC). However, the mechanism by which pemetrexed induces apoptosis remains unclear. In the present study, we investigated the involvement of reactive oxygen species (ROS) and sirtuin 1 (SIRT1) in pemetrexed-induced apoptosis in MSTO-211 malignant mesothelioma cells and A549 NSCLC cells. Pemetrexed enhanced caspase-dependent apoptosis, induced intracellular ROS generation, and downregulated SIRT1 in the MSTO-211 and A549 cells. Pemetrexed-induced apoptosis, which was prevented by pretreatment with N-acetyl-cysteine (NAC), was mediated by effects on the mitochondria, including mitochondrial membrane potential transition (MPT) and cytosolic release of cytochrome c, and also involved regulation of SIRT1 expression. Interference with SIRT1 expression using siRNA enhanced pemetrexed-induced apoptosis through mitochondrial dysfunction and ROS generation, whereas resveratrol, an activator of SIRT1, protected against pemetrexed-induced apoptosis. These results show that pemetrexed induces apoptosis in MSTO-211 mesothelioma cells and A549 NSCLC cells through mitochondrial dysfunction mediated by ROS accumulation and SIRT1 downregulation.
- Subjects :
- Mesothelioma
Cancer Research
Lung Neoplasms
Cell
Down-Regulation
Antineoplastic Agents
Apoptosis
Pemetrexed
Mitochondrion
Resveratrol
chemistry.chemical_compound
Sirtuin 1
Carcinoma, Non-Small-Cell Lung
Cell Line, Tumor
medicine
Humans
Membrane Potential, Mitochondrial
chemistry.chemical_classification
A549 cell
Reactive oxygen species
biology
Mesothelioma, Malignant
Cytochromes c
Free Radical Scavengers
General Medicine
Acetylcysteine
Mitochondria
respiratory tract diseases
medicine.anatomical_structure
Oncology
chemistry
biology.protein
Cancer research
Reactive Oxygen Species
medicine.drug
Subjects
Details
- ISSN :
- 17912431 and 1021335X
- Volume :
- 33
- Database :
- OpenAIRE
- Journal :
- Oncology Reports
- Accession number :
- edsair.doi.dedup.....4656f6689d00d6c2c21a4023b3c8dc13