title: Roles of aldo-keto reductases 1B10 and 1C3 and ATP-binding cassette transporter in docetaxel tolerance.
abstract: Docetaxel (DTX) is widely used for treatment of inveterate lung and prostate cancers, but its continuous administration elicits the hyposensitivity. Here, we established the DTX-resistant variants of human lung cancer A549 and androgen-independent prostate cancer Du145 cells and found that the resistance development provoked aberrant up-regulations of aldo-keto reductase (AKR) 1B10 and AKR1C3 in A549 and Du145 cells, respectively. In addition, the sensitivity to the DTX toxicity was significantly decreased and increased by overexpression and knockdown of the two AKR isoforms, respectively. Furthermore, the resistant cells exhibited a decreased level of reactive 4-hydroxy-2-nonenal formed during DTX treatment, and the decrease was alleviated by adding the AKR inhibitors, inferring that the two AKRs confer the chemoresistance through elevating the antioxidant properties. The development of DTX resistance was also associated with enhanced expression of an ATP-binding cassette (ABC) transporter ABCB1 among the ABC transporter isoforms. The combined treatment with inhibitors of the two AKRs and ABCB1 additively sensitized the resistant cells to DTX. Intriguingly, the AKR1B10 inhibitor also suppressed the lung cancer cross-resistance against cisplatin. The results suggest that combined treatment with AKRs (1B10 and 1C3) and ABCB1 inhibitors exerts overcoming effect against the cancer resistance to DTX and cisplatin, and can be used as the adjuvant therapy.
authors.affiliation: a Laboratory of Biochemistry, Gifu Pharmaceutical University , Gifu , Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Matsunaga
authors.affiliation: a Laboratory of Biochemistry, Gifu Pharmaceutical University , Gifu , Japan.
authors.forename: Haruhi
authors.initials: H
authors.lastname: Saito
authors.affiliation: a Laboratory of Biochemistry, Gifu Pharmaceutical University , Gifu , Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Endo
authors.affiliation: b Laboratory of Community Pharmacy, Gifu Pharmaceutical University , Gifu , Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Iguchi
authors.affiliation: c Laboratory of Pharmaceutics , Gifu Pharmaceutical University , Gifu , Japan.
authors.forename: Midori
authors.initials: M
authors.lastname: Soda
authors.affiliation: d Nagoya University Graduate School of Medicine , Nagoya , Japan.
authors.forename: Ossama
authors.initials: O
authors.lastname: El-Kabbani
authors.affiliation: e Faculty of Engineering , Gifu University , Gifu , Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Hara
authors.affiliation: a Laboratory of Biochemistry, Gifu Pharmaceutical University , Gifu , Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Ikari
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000449:Aldehyde Reductase / Q000378:metabolism*; D000074408:Aldo-Keto Reductases; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D000077143:Docetaxel; D006801:Humans; D043823:Taxoids / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D014162:Transfection
chemical_list: D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D043823:Taxoids; D000077143:Docetaxel; D000074408:Aldo-Keto Reductases; D000449:Aldehyde Reductase
keywords: ATP-binding cassette transporter B1; Aldo-keto reductase; androgen-independent prostate cancer; chemoresistance; docetaxel; lung cancer