Chemopreventive effect of tolfenamic acid on KB human cervical cancer cells and tumor xenograft by downregulating specificity protein 1.
Earlier studies have shown that tolfenamic acid (Tol) exhibits anticancer activity in several cancer models by inhibiting tumor growth and angiogenesis. However, the chemopreventive effect of Tol on a cervical cancer model and the underlying mechanism of action are unknown. In this study, Tol was found to inhibit cell proliferation by inducing apoptosis without affecting cyclo-oxygenase 2 expression, but ampiroxicam did not. Tol decreases the specificity protein 1 (Sp1) mRNA and its promoter activity in KB cervical cancer cells, and the downregulation of Sp1 protein by affecting several proteins that contain GC-rich sites on their promoters. Studies using small interference RNA and an Sp1-specific inhibitor (mithramycin A) confirmed that the decrease in Sp1 by Tol affects survivin and p27. Tol also inhibited tumor growth and Sp1 protein in athymic nude mice xenografts. These results show that Tol could be a potent anticervical cancer drug that acts by regulating Sp1 protein and its downstream pathways.
Departments of Oral Pathology, School of Dentistry and Institute of Oral Bioscience, BK21 Project, Chonbuk National University, Jeonju, Republic of Korea.
Jung-Hyun
JH
Shim
Ji-Ae
JA
Shin
Ji-Youn
JY
Jung
Kyeong-Hee
KH
Choi
Eun-Sun
ES
Choi
Nam-Pyo
NP
Cho
Gu
G
Kong
Mi Heon
MH
Ryu
Jung-Ii
JI
Chae
Sung-Dae
SD
Cho
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016329:Sp1 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays; D062367:ortho-Aminobenzoates / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D012333:RNA, Messenger; D016329:Sp1 Transcription Factor; D062367:ortho-Aminobenzoates; C009500:tolfenamic acid; D008156:Luciferases