Induction of aldo-keto reductases (AKR1C1 and AKR1C3) abolishes the efficacy of daunorubicin chemotherapy for leukemic U937 cells

Toshiyuki Matsunaga, Ayano Yamaguchi, Yoshifumi Morikawa, Chihiro Kezuka, Hiroaki Takazawa, Satoshi Endo, Ossama El-Kabbani, Kazuo Tajima, Akira Ikari, Akira Hara

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Abstract

Continuous exposure to daunorubicin (DNR) confers resistance against the drug-elicited lethality of leukemic cells and then reduces the remission rate. However, the detailed mechanisms involved in resistance development of leukemic cells to DNR remain unclear. Upregulation of aldo-keto reductases (AKRs) in human leukemic U937 cells was evaluated by gene-specific PCR and western blot analyses, and the contribution of AKRs toward the DNR sensitivity was assessed using gene expression and RNA-interference techniques and specific inhibitors. In addition, DNR reduction and cell differentiation were analyzed by fluorescence high-performance liquid chromatography and flow cytometry, respectively. Treatment with high doses of DNR triggered apoptotic induction of U937 cells through the production of reactive oxygen species (ROS) and a ROS-dependent mechanism. In contrast, DNR, at its sublethal doses, induced the expression of AKR1C1 and AKR1C3, both of which reduced the DNR sensitivity of the cells. The enzymes did not interfere with the cell differentiation caused by DNR, whereas their upregulation facilitated reduction of the anticancer drug and a ROS-derived lipid aldehyde 4-hydroxy-2-nonenal. These results suggest crucial roles of AKR1C1 and AKR1C3 in the acquisition of DNR resistance of leukemic cells by metabolizing both DNR and cytotoxic aldehydes derived from ROS-linked lipid peroxidation.
Original languageEnglish
Pages (from-to)868 - 877
Number of pages10
JournalAnti-Cancer Drugs
Volume25
Issue number8
DOIs
Publication statusPublished - 2014

Cite this

Matsunaga, Toshiyuki ; Yamaguchi, Ayano ; Morikawa, Yoshifumi ; Kezuka, Chihiro ; Takazawa, Hiroaki ; Endo, Satoshi ; El-Kabbani, Ossama ; Tajima, Kazuo ; Ikari, Akira ; Hara, Akira. / Induction of aldo-keto reductases (AKR1C1 and AKR1C3) abolishes the efficacy of daunorubicin chemotherapy for leukemic U937 cells. In: Anti-Cancer Drugs. 2014 ; Vol. 25, No. 8. pp. 868 - 877.
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abstract = "Continuous exposure to daunorubicin (DNR) confers resistance against the drug-elicited lethality of leukemic cells and then reduces the remission rate. However, the detailed mechanisms involved in resistance development of leukemic cells to DNR remain unclear. Upregulation of aldo-keto reductases (AKRs) in human leukemic U937 cells was evaluated by gene-specific PCR and western blot analyses, and the contribution of AKRs toward the DNR sensitivity was assessed using gene expression and RNA-interference techniques and specific inhibitors. In addition, DNR reduction and cell differentiation were analyzed by fluorescence high-performance liquid chromatography and flow cytometry, respectively. Treatment with high doses of DNR triggered apoptotic induction of U937 cells through the production of reactive oxygen species (ROS) and a ROS-dependent mechanism. In contrast, DNR, at its sublethal doses, induced the expression of AKR1C1 and AKR1C3, both of which reduced the DNR sensitivity of the cells. The enzymes did not interfere with the cell differentiation caused by DNR, whereas their upregulation facilitated reduction of the anticancer drug and a ROS-derived lipid aldehyde 4-hydroxy-2-nonenal. These results suggest crucial roles of AKR1C1 and AKR1C3 in the acquisition of DNR resistance of leukemic cells by metabolizing both DNR and cytotoxic aldehydes derived from ROS-linked lipid peroxidation.",
author = "Toshiyuki Matsunaga and Ayano Yamaguchi and Yoshifumi Morikawa and Chihiro Kezuka and Hiroaki Takazawa and Satoshi Endo and Ossama El-Kabbani and Kazuo Tajima and Akira Ikari and Akira Hara",
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language = "English",
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Matsunaga, T, Yamaguchi, A, Morikawa, Y, Kezuka, C, Takazawa, H, Endo, S, El-Kabbani, O, Tajima, K, Ikari, A & Hara, A 2014, 'Induction of aldo-keto reductases (AKR1C1 and AKR1C3) abolishes the efficacy of daunorubicin chemotherapy for leukemic U937 cells', Anti-Cancer Drugs, vol. 25, no. 8, pp. 868 - 877. https://doi.org/10.1097/CAD.0000000000000112

Induction of aldo-keto reductases (AKR1C1 and AKR1C3) abolishes the efficacy of daunorubicin chemotherapy for leukemic U937 cells. / Matsunaga, Toshiyuki; Yamaguchi, Ayano; Morikawa, Yoshifumi; Kezuka, Chihiro; Takazawa, Hiroaki; Endo, Satoshi; El-Kabbani, Ossama; Tajima, Kazuo; Ikari, Akira; Hara, Akira.

In: Anti-Cancer Drugs, Vol. 25, No. 8, 2014, p. 868 - 877.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Induction of aldo-keto reductases (AKR1C1 and AKR1C3) abolishes the efficacy of daunorubicin chemotherapy for leukemic U937 cells

AU - Matsunaga, Toshiyuki

AU - Yamaguchi, Ayano

AU - Morikawa, Yoshifumi

AU - Kezuka, Chihiro

AU - Takazawa, Hiroaki

AU - Endo, Satoshi

AU - El-Kabbani, Ossama

AU - Tajima, Kazuo

AU - Ikari, Akira

AU - Hara, Akira

PY - 2014

Y1 - 2014

N2 - Continuous exposure to daunorubicin (DNR) confers resistance against the drug-elicited lethality of leukemic cells and then reduces the remission rate. However, the detailed mechanisms involved in resistance development of leukemic cells to DNR remain unclear. Upregulation of aldo-keto reductases (AKRs) in human leukemic U937 cells was evaluated by gene-specific PCR and western blot analyses, and the contribution of AKRs toward the DNR sensitivity was assessed using gene expression and RNA-interference techniques and specific inhibitors. In addition, DNR reduction and cell differentiation were analyzed by fluorescence high-performance liquid chromatography and flow cytometry, respectively. Treatment with high doses of DNR triggered apoptotic induction of U937 cells through the production of reactive oxygen species (ROS) and a ROS-dependent mechanism. In contrast, DNR, at its sublethal doses, induced the expression of AKR1C1 and AKR1C3, both of which reduced the DNR sensitivity of the cells. The enzymes did not interfere with the cell differentiation caused by DNR, whereas their upregulation facilitated reduction of the anticancer drug and a ROS-derived lipid aldehyde 4-hydroxy-2-nonenal. These results suggest crucial roles of AKR1C1 and AKR1C3 in the acquisition of DNR resistance of leukemic cells by metabolizing both DNR and cytotoxic aldehydes derived from ROS-linked lipid peroxidation.

AB - Continuous exposure to daunorubicin (DNR) confers resistance against the drug-elicited lethality of leukemic cells and then reduces the remission rate. However, the detailed mechanisms involved in resistance development of leukemic cells to DNR remain unclear. Upregulation of aldo-keto reductases (AKRs) in human leukemic U937 cells was evaluated by gene-specific PCR and western blot analyses, and the contribution of AKRs toward the DNR sensitivity was assessed using gene expression and RNA-interference techniques and specific inhibitors. In addition, DNR reduction and cell differentiation were analyzed by fluorescence high-performance liquid chromatography and flow cytometry, respectively. Treatment with high doses of DNR triggered apoptotic induction of U937 cells through the production of reactive oxygen species (ROS) and a ROS-dependent mechanism. In contrast, DNR, at its sublethal doses, induced the expression of AKR1C1 and AKR1C3, both of which reduced the DNR sensitivity of the cells. The enzymes did not interfere with the cell differentiation caused by DNR, whereas their upregulation facilitated reduction of the anticancer drug and a ROS-derived lipid aldehyde 4-hydroxy-2-nonenal. These results suggest crucial roles of AKR1C1 and AKR1C3 in the acquisition of DNR resistance of leukemic cells by metabolizing both DNR and cytotoxic aldehydes derived from ROS-linked lipid peroxidation.

UR - http://dx.doi.org/10.1097/CAD.0000000000000112

U2 - 10.1097/CAD.0000000000000112

DO - 10.1097/CAD.0000000000000112

M3 - Article

VL - 25

SP - 868

EP - 877

JO - Anti-Cancer Drugs

JF - Anti-Cancer Drugs

SN - 0959-4973

IS - 8

ER -