Tolfenamic acid induces apoptosis and growth inhibition in anaplastic thyroid cancer: Involvement of nonsteroidal anti-inflammatory drug-activated gene-1 expression and intracellular reactive oxygen species generation.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are usually used for the treatment of inflammatory diseases. However, certain NSAIDs also have antitumor activities in various cancers, including head and neck cancer, through cyclooxygenase-dependent or independent pathways. Nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1), a TGF-β superfamily protein, is induced by NSAIDs and has been shown to be induced by several antitumorigenic compounds and to exhibit proapoptotic and antitumorigenic activities. In this report, we demonstrate for the first time that tolfenamic acid (TA) transcriptionally induced the expression of NAG-1 during TA-induced apoptosis of anaplastic thyroid cancer (ATC) cells. TA reduced the viability of ATC cells in a dose-dependent manner and induced apoptosis, findings that were coincident with NAG-1 expression. Overexpression of the NAG-1 gene using cDNA enhanced the apoptotic effect of TA, whereas suppression of NAG-1 expression by small interfering RNA attenuated TA-induced apoptosis. Subsequently, we found that intracellular ROS generation plays an important role in activating the proapoptotic protein NAG-1. Then, we confirmed antitumorigenic effects of TA in a nude mouse orthotopic ATC model, and this result accompanied the augmentation of NAG-1 expression and ROS generation in tumor tissue. Taken together, these results demonstrate that TA induces apoptosis via NAG-1 expression and ROS generation in in vitro and in vivo ATC models, providing a novel mechanistic explanation and indicating a potential chemotherapeutic approach for treatment of ATC.
Department of Otolaryngology, School of Medicine, Ajou University, Suwon 442-749, Korea; Center for Cell Death-Regulating Biodrugs, School of Medicine, Ajou University, Suwon 442-749, Korea.
Jae Won
JW
Chang
Department of Otolaryngology, School of Medicine, Ajou University, Suwon 442-749, Korea; Center for Cell Death-Regulating Biodrugs, School of Medicine, Ajou University, Suwon 442-749, Korea.
Sung Un
SU
Kang
Department of Otolaryngology, School of Medicine, Ajou University, Suwon 442-749, Korea; Center for Cell Death-Regulating Biodrugs, School of Medicine, Ajou University, Suwon 442-749, Korea.
Jae Won
JW
Choi
Department of Otolaryngology, School of Medicine, Ajou University, Suwon 442-749, Korea; Center for Cell Death-Regulating Biodrugs, School of Medicine, Ajou University, Suwon 442-749, Korea.
Yoo Seob
YS
Shin
Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996, USA.
Seung Joon
SJ
Baek
Department of Nutrition and Food Science, College of Agriculture and Natural Resources, University of Maryland, College Park, MD 20742, USA.
Seong-Ho
SH
Lee
Department of Otolaryngology, School of Medicine, Ajou University, Suwon 442-749, Korea; Center for Cell Death-Regulating Biodrugs, School of Medicine, Ajou University, Suwon 442-749, Korea. Electronic address: ostium@ajou.ac.kr.
Chul-Ho
CH
Kim
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic; D055436:Growth Differentiation Factor 15 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction; D065646:Thyroid Carcinoma, Anaplastic / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D062367:ortho-Aminobenzoates / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D062367:ortho-Aminobenzoates; C009500:tolfenamic acid
Anaplastic thyroid cancer; Apoptosis; Free radicals; NAG-1; Nonsteroidal anti-inflammatory drug-activated gene-1; Tolfenamic acid; reactive oxygen species