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.
MeSH terms
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20-Hydroxysteroid Dehydrogenases / antagonists & inhibitors
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20-Hydroxysteroid Dehydrogenases / biosynthesis*
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20-Hydroxysteroid Dehydrogenases / genetics
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3-Hydroxysteroid Dehydrogenases / antagonists & inhibitors
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3-Hydroxysteroid Dehydrogenases / biosynthesis*
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3-Hydroxysteroid Dehydrogenases / genetics
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Aldo-Keto Reductase Family 1 Member C3
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Cisplatin / administration & dosage
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Drug Resistance, Neoplasm / drug effects
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Fluorouracil / administration & dosage
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Gene Expression Regulation, Neoplastic / drug effects
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HeLa Cells
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Humans
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Hydroxyprostaglandin Dehydrogenases / antagonists & inhibitors
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Hydroxyprostaglandin Dehydrogenases / biosynthesis*
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Hydroxyprostaglandin Dehydrogenases / genetics
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Hydroxysteroid Dehydrogenases / antagonists & inhibitors
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Hydroxysteroid Dehydrogenases / biosynthesis*
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Hydroxysteroid Dehydrogenases / genetics
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Mefenamic Acid / administration & dosage*
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Neoplasms / drug therapy*
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Neoplasms / genetics
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Neoplasms / pathology
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Oxidoreductases
Substances
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Mefenamic Acid
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Oxidoreductases
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3-Hydroxysteroid Dehydrogenases
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Hydroxysteroid Dehydrogenases
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20-Hydroxysteroid Dehydrogenases
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3 alpha-beta, 20 beta-hydroxysteroid dehydrogenase
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Hydroxyprostaglandin Dehydrogenases
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AKR1C2 protein, human
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AKR1C3 protein, human
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Aldo-Keto Reductase Family 1 Member C3
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trans-1,2-dihydrobenzene-1,2-diol dehydrogenase
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Cisplatin
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Fluorouracil