PX-12 induces apoptosis in Calu-6 cells in an oxidative stress-dependent manner.
PX-12 (1-methylpropyl 2-imidazolyl disulfide) as a thioredoxin (Trx) inhibitor has an anti-tumor effect. However, there is no report about the toxicological effect of PX-12 on lung cancer cells. Here, we investigated the anti-growth effects of PX-12 on Calu-6 lung cancer cells in relation to reactive oxygen species (ROS) and glutathione (GSH) levels. PX-12 induced the growth inhibition of Calu-6 cells with IC50 of nearly 3 μM at 72 h. In contrast, PX-12 did not affect the growth of human small airway epithelial cells (HSAECs). Cell cycle distribution analysis indicated that PX-12 significantly induced a G2/M phase arrest in Calu-6 cells. PX-12 also increased the number of annexin V-FITC-positive cells in Calu-6 cells. All the tested caspase inhibitors markedly prevented Calu-6 cell death induced by PX-12. With regard to ROS and GSH levels, PX-12 increased ROS levels containing O2(·-) in Calu-6 cells and induced the depletion of GSH. N-acetyl cysteine (NAC), which is a well-known antioxidant, significantly reduced O2(·-) level in PX-12-treated Calu-6 cells and prevented apoptosis and GSH depletion in these cells. In conclusion, it is the first report that PX-12 inhibited the growth of Calu-6 cells via a G2/M phase arrest as well as apoptosis, which effect was related to the intracellular increases in ROS levels.
Department of Physiology, Medical School, Research Institute for Endocrine Sciences, Chonbuk National University, JeonJu, 561-180, Republic of Korea.
Bo Ra
BR
You
Hye Rim
HR
Shin
Bo Ram
BR
Han
Woo Hyun
WH
Park
D000111:Acetylcysteine / Q000378:metabolism; D017304:Annexin A5 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004220:Disulfides / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives / Q000378:metabolism; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism
D017304:Annexin A5; D000970:Antineoplastic Agents; D000975:Antioxidants; D004220:Disulfides; C492760:FITC-annexin A5; D007093:Imidazoles; D017382:Reactive Oxygen Species; C412893:1-methylpropyl-2-imidazolyl disulfide; D005978:Glutathione; D016650:Fluorescein-5-isothiocyanate; D000111:Acetylcysteine