Significance of aldo-keto reductase 1C3 and ATP-binding cassette transporter B1 in gain of irinotecan resistance in colon cancer cells

• Published in: Chemico-biological interactions 2020-12, Vol.332, p.109295, Article 109295
• Main Authors: Matsunaga, Toshiyuki, Okumura, Naoko, Saito, Haruhi, Morikawa, Yoshifumi, Suenami, Koichi, Hisamatsu, Aki, Endo, Satoshi, Ikari, Akira
• Format: Article
• Language: English
• Subjects: Aldehydes - metabolism; Aldo-keto reductase 1C3; Aldo-Keto Reductase Family 1 Member C3 - metabolism; ATP Binding Cassette Transporter, Subfamily B - metabolism; ATP-Binding cassette B1; Cell Line, Tumor; Chemoresistance; Colon cancer; Colonic Neoplasms - genetics; Colonic Neoplasms - metabolism; Drug Resistance, Neoplasm - drug effects; Gene Expression Regulation, Neoplastic - drug effects; Humans; Irinotecan; Irinotecan - metabolism; Irinotecan - pharmacology; Pregnane-X receptor; Up-Regulation - drug effects
• ISSN: 0009-2797; 1872-7786
• DOI: 10.1016/j.cbi.2020.109295

Irinotecan (CPT11) is widely prescribed for treatment of various intractable cancers such as advanced and metastatic colon cancer cells, but its continuous treatment promotes the resistance development. In this study, we established CPT11-resistant variants of three human colon cancer (DLD1, RKO and LoVo) cell lines, and found that gain of the resistance elicited an up-regulation of aldo-keto reductase (AKR) 1C3 in the cells. Additionally, the sensitivity to CPT11 toxicity was decreased and increased by overexpression and knockdown, respectively, of the enzyme. Moreover, the resistant cells suppressed formation of reactive 4-hydroxy-2-nonenal by CPT11 treatment, and the suppressive effect was almost completely abolished by addition of an AKR1C3 inhibitor. These results suggest that up-regulated AKR1C3 contributes to promotion of the chemoresistance by detoxifying the reactive aldehyde. Western blot and real-time polymerase-chain reaction analyses and ATP-binding cassette (ABC) B1-functional assay revealed that, among three ABC transporters, ABCB1 was the most highly up-regulated by development of the CPT11 resistance, inferring a significant contribution of pregnane-X receptor-dependent signaling to the ABCB1 up-regulation. The combined treatment with inhibitors of AKR1C3 and ABCB1 potently sensitized the resistant cells to CPT11 and its active metabolite SN38. Taken together, our results suggest that combination of AKR1C3 and ABCB1 inhibitors is effective as adjuvant therapy to enhance CPT11 sensitivity of intractable colon cancer cells. [Display omitted] •Gain of CPT11 resistance up-regulates AKR1C3 expression in colon cancer cells.•AKR1C3 accelerates the resistance through metabolizing cytotoxic HNE.•The CPT11 resistance is also ascribed to the ABCB1 up-regulation via PXR activation.•Treatment with inhibitors of AKR1C3 and ABCB1 overcomes the CPT11 resistance.•Author statement.