title: Mefenamic acid enhances anticancer drug sensitivity via inhibition of aldo-keto reductase 1C enzyme activity.
abstract: Resistance to anticancer medications often leads to poor outcomes. The present study explored an effective approach for enhancing chemotherapy targeted against human cancer cells. Real-time quantitative real-time polymerase chain reaction (qRT-PCR) analysis revealed overexpression of members of aldo-keto reductase (AKR) 1C family, AKR1C1, AKR1C2, AKR1C3, and AKR1C4, in cisplatin, cis-diamminedichloroplatinum (II) (CDDP)-resistant human cancer cell lines, HeLa (cervical cancer cells) and Sa3 (oral squamous cell carcinoma cells). The genes were downregulated using small-interfering RNA (siRNA) transfection, and the sensitivity to CDDP or 5-fluorouracil (5-FU) was investigated. When the genes were knocked down, sensitivity to CDDP and 5-FU was restored. Furthermore, we found that administration of mefenamic acid, a widely used non-steroidal anti-inflammatory drug (NSAID) and a known inhibitor of AKR1Cs, enhanced sensitivity to CDDP and 5-FU. The present study suggests that AKR1C family is closely associated with drug resistance to CDDP and 5-FU, and mefenamic acid enhances their sensitivity through its inhibitory activity in drug-resistant human cancer cells. Thus, the use of mefenamic acid to control biological function of AKR1C may lead to effective clinical outcomes by overcoming anticancer drug resistance.
authors.affiliation: Department of Oral Science, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8670, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Shiiba
authors.affiliation: Department of Oral Science, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8670, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Yamagami
authors.affiliation: Department of Oral Science, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8670, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Yamamoto
authors.affiliation: Department of Oral Science, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8670, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Minakawa
authors.affiliation: Department of Oral Science, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8670, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Okamoto
authors.affiliation: Department of Oral Science, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8670, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kasamatsu
authors.affiliation: Department of Oral Science, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8670, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Sakamoto
authors.affiliation: Department of Oral Science, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8670, Japan.
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Uzawa
authors.affiliation: Department of Medical Oncology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8670, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Takiguchi
authors.affiliation: Department of Oral Science, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8670, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Tanzawa
mesh_terms: D015089:20-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D015096:3-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D000074425:Aldo-Keto Reductase Family 1 Member C3; D002945:Cisplatin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005472:Fluorouracil / Q000008:administration & dosage; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D006913:Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D008528:Mefenamic Acid / Q000008:administration & dosage*; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010088:Oxidoreductases; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)
chemical_list: D015089:20-Hydroxysteroid Dehydrogenases; D015096:3-Hydroxysteroid Dehydrogenases; D000074425:Aldo-Keto Reductase Family 1 Member C3; D002945:Cisplatin; D005472:Fluorouracil; D006911:Hydroxyprostaglandin Dehydrogenases; D006913:Hydroxysteroid Dehydrogenases; D008528:Mefenamic Acid; D010088:Oxidoreductases; C115140:3 alpha-beta, 20 beta-hydroxysteroid dehydrogenase; C435496:AKR1C2 protein, human; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific); C487341:AKR1C3 protein, human; C048338:trans-1,2-dihydrobenzene-1,2-diol dehydrogenase