Mefenamic acid enhances anticancer drug sensitivity via inhibition of aldo-keto reductase 1C enzyme activity

Oncol Rep. 2017 Apr;37(4):2025-2032. doi: 10.3892/or.2017.5480. Epub 2017 Mar 1.


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.

MeSH terms

  • 20-Hydroxysteroid Dehydrogenases / antagonists & inhibitors
  • 20-Hydroxysteroid Dehydrogenases / biosynthesis*
  • 20-Hydroxysteroid Dehydrogenases / genetics
  • 3-Hydroxysteroid Dehydrogenases / antagonists & inhibitors
  • 3-Hydroxysteroid Dehydrogenases / biosynthesis*
  • 3-Hydroxysteroid Dehydrogenases / genetics
  • Aldo-Keto Reductase Family 1 Member C3
  • Cisplatin / administration & dosage
  • Drug Resistance, Neoplasm / drug effects
  • Fluorouracil / administration & dosage
  • Gene Expression Regulation, Neoplastic / drug effects
  • HeLa Cells
  • Humans
  • Hydroxyprostaglandin Dehydrogenases / antagonists & inhibitors
  • Hydroxyprostaglandin Dehydrogenases / biosynthesis*
  • Hydroxyprostaglandin Dehydrogenases / genetics
  • Hydroxysteroid Dehydrogenases / antagonists & inhibitors
  • Hydroxysteroid Dehydrogenases / biosynthesis*
  • Hydroxysteroid Dehydrogenases / genetics
  • Mefenamic Acid / administration & dosage*
  • Neoplasms / drug therapy*
  • Neoplasms / genetics
  • Neoplasms / pathology
  • Oxidoreductases


  • Mefenamic Acid
  • Oxidoreductases
  • 3-Hydroxysteroid Dehydrogenases
  • Hydroxysteroid Dehydrogenases
  • 20-Hydroxysteroid Dehydrogenases
  • 3 alpha-beta, 20 beta-hydroxysteroid dehydrogenase
  • Hydroxyprostaglandin Dehydrogenases
  • AKR1C2 protein, human
  • AKR1C3 protein, human
  • Aldo-Keto Reductase Family 1 Member C3
  • trans-1,2-dihydrobenzene-1,2-diol dehydrogenase
  • Cisplatin
  • Fluorouracil