Naturally Occurring Variants of Human Aldo-Keto Reductases with Reduced In Vitro Metabolism of Daunorubicin and Doxorubicin

Bains, Onkar S.; Grigliatti, Thomas A.; Reid, Ronald E.; Riggs, K. Wayne

doi:10.1124/jpet.110.173179

Cited by 90 publications

(77 citation statements)

References 39 publications

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“…Tumors increase or acquire resistance to doxorubicin in several ways, including (i) increased expression of drug transporters (26), (ii) enhancement of doxorubicin metabolism (27), and (iii) alteration of intracellular localization of doxorubicin (28). Doxorubicin is deactivated by several carbonyl reducing enzymes, including carbonyl reductases (e.g., CBR1 and CBR3) (29,30) and aldo-keto reductases (e.g., AKR1A1, AKR1B10, AKR1C3, and AKR1C4) (31)(32)(33). CBR1 activities are increased in human lung and breast cancer tissues (21).…”

Section: Discussionmentioning

confidence: 99%

Resveratrol Reduces the Hypoxia-Induced Resistance to Doxorubicin in Breast Cancer Cells

Mitani

Ito

Harada

et al. 2014

J Nutr Sci Vitaminol

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Summary Resveratrol (3,4′,5-trihydroxy-trans-stilbene) is known to enhance the cytotoxicity of the anticancer drug doxorubicin. On the other hand, breast cancer MCF-7 cells acquire resistance to doxorubicin under hypoxic conditions. In this study, we investigated the effect of resveratrol on hypoxia-induced resistance to doxorubicin in MCF-7 cells. Resveratrol and its derivative 3,5-dihydroxy-4′-methoxy-trans-stilbene, but not 3,5-dimethoxy-4′-hydroxy-trans-stilbene, cancelled hypoxia-induced resistance to doxorubicin at a concentration of 10 mm. Carbonyl reductase 1 (CBR1) catalyzes the conversion of doxorubicin to its metabolite doxorubicinol, which is much less effective than doxorubicin. Hypoxia increased the expression of CBR1 at both mRNA and protein levels, and knockdown of CBR1 inhibited hypoxia-induced resistance to doxorubicin in MCF-7 cells. Knockdown of hypoxiainducible factor (HIF)-1a repressed the hypoxia-induced expression of CBR1. Resveratrol repressed the expression of HIF-1a protein, but not HIF-1a mRNA, and decreased hypoxiaactivated HIF-1 activity. Resveratrol repressed the hypoxia-induced expression of CBR1 at both mRNA and protein levels. Likewise, 3,5-dihydroxy-4′-methoxy-trans-stilbene decreased the hypoxia-induced expression of CBR1 protein, but not 3,5-dimethoxy-4′-hydroxy-transstilbene. Furthermore, resveratrol decreased the expression of HIF-1a protein even in the presence of the proteasome inhibitor MG132 in hypoxia. Theses results indicate that in MCF-7 cells, HIF-1a-increased CBR1 expression plays an important role in hypoxia-induced resistance to doxorubicin and that resveratrol and 3,5-dihydroxy-4′-methoxy-trans-stilbene decrease CBR1 expression by decreasing HIF-1a protein expression, perhaps through a proteasome-independent pathway, and consequently repress hypoxia-induced resistance to doxorubicin.

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Section: Discussionmentioning

confidence: 99%

Resveratrol Reduces the Hypoxia-Induced Resistance to Doxorubicin in Breast Cancer Cells

Mitani

Ito

Harada

et al. 2014

J Nutr Sci Vitaminol

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“…In addition, the k cat /K m value for ONE 13) is 110-fold higher than that for DOX. 38) The positive relationship between detoxification activity towards the reactive aldehydes (ONE and HNE) and chemoresistance development is consistent with that of colon cancer cells resistant to mitomycin-C and cisplatin, both of which generate ROS as their anticancer mechanism. 54,55) In addition, considering that progression of DOX resistance in gastric cancer cells is closely linked to manganese superoxide dismutase, 6) it is reasonable to assume that elevation of cytoprotective activities against ROS and the resultant reactive aldehydes such as ONE is one of the most crucial steps in the development of DOX resistance in gastrointestinal cancer cells.…”

Section: Discussionmentioning

confidence: 57%

“…CBR1 exhibits reductase activity toward DOX and is considered to be the predominant DOX reductase in human liver, 49) whereas its K m value for DOX (167 49) or 540 µM 38) ) is substantially higher than the blood concentration (0.1 to 1 µM) detected in patients who received the chemotherapy. 53) Under our assay conditions using DOX at the low concentration (10 µM), recombinant CBR1 (less than 100 µg) and the overexpression into LoVo cells hardly reduced DOX into its C-13 alcohol metabolite DOXol.…”

Section: Discussionmentioning

confidence: 99%

“…6A), the major metabolic enzyme is not identified yet. Since three AKRs (1C1, 1C3 and 1B10) are reported to be also Nrf2-driven genes 56,57) and to reduce the anthracycline drugs into their corresponding alcohols, 38,49) further studies in our laboratory are underway to define pathophysiological roles of the four AKRs in development of the chemoresistant gastrointestinal cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…9,38) To elucidate whether CBR1 up-regulated during acquisition of the DOX resistance decreases chemosensitivity of cells via its catalytic conversion of DOX into DOXol, we first compared the DOX reductase activities in the resistant (LoVo-R and MKN-R) and parental (LoVo and MKN45) cells. The activities in the resistant cells were more than 2-fold higher than those in the parental cells (Fig.…”

Section: Effects Of Cbr1 Inhibitor Que On Dox Resistancementioning

confidence: 99%

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Up-Regulation of Carbonyl Reductase 1 Renders Development of Doxorubicin Resistance in Human Gastrointestinal Cancers

Matsunaga

Kezuka

Morikawa

et al. 2015

Biological & Pharmaceutical Bulletin

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Doxorubicin (DOX) is widely used for the treatment of a wide range of cancers such as breast and lung cancers, and malignant lymphomas, but is generally less efficacious in gastrointestinal cancers. The most accepted explanation for the DOX refractoriness is its resistance development. Here, we established DOX-resistant phenotypes of human gastric MKN45 and colon LoVo cells by continuous exposure to incremental concentrations of the drug. While the parental MKN45 and LoVo cells expressed carbonyl reductase 1 (CBR1) highly and moderately, respectively, the gain of DOX resistance further elevated the CBR1 expression. Additionally, the DOX-elicited cytotoxicity was lowered by overexpression of CBR1 and inversely strengthened by knockdown of the enzyme using small interfering RNA or pretreating with the specific inhibitor quercetin, which also reduced the DOX refractoriness of the two resistant cells. These suggest that CBR1 is a key enzyme responsible for the DOX resistance of gastrointestinal cancer cells and that its inhibitor is useful in the adjuvant therapy. Although CBR1 is known to metabolize DOX to a less toxic anticancer metabolite doxorubicinol, its overexpression in the parental cells hardly show significant reductase activity toward low concentration of DOX. In contrast, the overexpression of CBR1 increased the reductase activity toward an oxidative stress-derived cytotoxic aldehyde 4-oxo-2-nonenal. The sensitivity of the DOX-resistant cells to 4-oxo-2-nonenal was lower than that of the parental cells, and the resistance-elicited hyposensitivity was almost completely ameliorated by addition of the CBR1 inhibitor. Thus, CBR1 may promote development of DOX resistance through detoxification of cytotoxic aldehydes, rather than the drug's metabolism.Key words carbonyl reductase 1; doxorubicin; drug resistance; gastrointestinal cancer cell; quercetin An anthracycline-based antibiotic doxorubicin (DOX) is widely utilized for the treatment of patients not only with solid tumors formed in many organs including breast, lung and stomach, but also with malignant lymphomas. 1) One of the major anticancer actions of DOX is intercalation into the double-stranded DNA and the resultant inhibition of DNA/RNA polymerases.1) In addition, treatment with the drug is known to form the tripartite complex with DNA and topoisomerase-II, ultimately blocking the transcription and replication of DNA. Besides the events essential for protein biosynthesis and cell proliferation, the free radical formation is proposed as another cytolethal mechanism triggered by DOX.1-3) Cellular reductases such as cytochrome P450 reductase 4) and xanthine oxidase 5) catalyze the one-electron reduction of the p-quinone structure in the anthraquinone ring of DOX into a semiquinone radical intermediate, which in turn reacts with molecular oxygen to yield superoxide anion radical. The radical is further converted into a more potent oxidizing agent hydroxyl radical, and thereby oxidatively modifies intracellular components such as nucleic acids, lipids an...

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DNA Topoisomerase Targeting Drugs

Thomas

Bates

Figg

et al. 2017

Holland‐Frei Cancer Medicine

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Overview DNA topoisomerase targeting drugs are widely used in the treatment of multiple cancers. These drugs act by generating topoisomerase‐linked DNA breaks and by blocking the religation of the cleavage complexes. Although topoisomerase targeting drugs have a wide spectrum of activity, structural, pharmacokinetic, and pharmacodynamic characteristics somewhat limit their efficacy and safety. To circumvent these limitations and to further exploit its activity, newer inhibitors‐ including novel formulations and those that achieve targeted delivery‐ are being developed. Recently described mechanisms that underlie cellular sensitivity to these agents will enable us to predict the activity of topoisomerase targeting drugs and to precisely select patients who are most likely to benefit. Understanding the genetic variants in drug metabolizing enzymes, transporters, and other proteins that influence the pharmacology of these drugs will allow for further individualizing the use of these drugs.

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Naturally Occurring Variants of Human Aldo-Keto Reductases with Reduced In Vitro Metabolism of Daunorubicin and Doxorubicin

Cited by 90 publications

References 39 publications

Resveratrol Reduces the Hypoxia-Induced Resistance to Doxorubicin in Breast Cancer Cells

Resveratrol Reduces the Hypoxia-Induced Resistance to Doxorubicin in Breast Cancer Cells

Up-Regulation of Carbonyl Reductase 1 Renders Development of Doxorubicin Resistance in Human Gastrointestinal Cancers

DNA Topoisomerase Targeting Drugs

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