title: Reactive oxygen species mediate tolfenamic acid-induced apoptosis in human colorectal cancer cells.
abstract: Several studies have shown substantial evidences that non-steroidal anti-inflammatory drugs (NSAIDs) exert anticancer effects by generating reactive oxygen species (ROS). Tolfenamic acid (TA) is one of the traditional NSAIDs widely used for treatment of migraine. TA has anti-cancer activities in several human cancer models. In this study, we report that generation of ROS by TA leads to apoptosis through modulation of several pathways in human colorectal cancer cells. TA induced rapid generation of intracellular ROS and led to an increase of phosphorylation of H2AX, a tail moment of comet and distribution of fragmented genomic DNA traces. Treatment of N-acetyl-l-cysteine (NAC) abolished TA-induced phosphorylation of H2AX and apoptosis. Treatment of TA resulted in an increase of nuclear factor-kappaB (NF-κB) transcriptional activity through inhibitor of kappa B (IκB-α) degradation and subsequent p65 nuclear translocation. In addition, TA increased apoptosis-inducing activating transcription factor 3 (ATF3) expression. However, the treatment of NAC abolished TA-mediated NF-κB activation and ATF3 expression and chemical inhibition of NF-κB or knockdown of p65 significantly attenuated TA-induced ATF3 expression. Our finding indicates that ROS-mediated DNA damage and subsequent activation of NF-κB and ATF3 expression plays a significant role in TA-induced apoptosis in human colorectal cancer cells.
authors.affiliation: Department of Nutrition and Food Science, College of Agriculture and Natural Resources, University of Maryland, College Park, MD 20742, USA.
authors.forename: Jin Boo
authors.initials: JB
authors.lastname: Jeong
authors.forename: Jieun
authors.initials: J
authors.lastname: Choi
authors.forename: Seung Joon
authors.initials: SJ
authors.lastname: Baek
authors.forename: Seong-Ho
authors.initials: SH
authors.lastname: Lee
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D004249:DNA Damage; D006801:Humans; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D062367:ortho-Aminobenzoates
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D062367:ortho-Aminobenzoates; C009500:tolfenamic acid
keywords: Apoptosis; DNA damage; Reactive oxygen species; Tolfenamic acid