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.

Abstract

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-beta 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.