The aldo-keto reductase AKR1C3 contributes to 7,12-dimethylbenz(a)anthracene-3,4-dihydrodiol mediated oxidative DNA damage in myeloid cells: Implications for leukemogenesis

Birtwistle, Jane; Hayden, Rachel E.; Khanim, Farhat L.; Green, Richard M.; Pearce, Claire; Davies, Nick; Wake, N.; Schrewe, Heinrich; Ride, J.P.; Chipman, J.K.; Bunce, Christopher M.

doi:10.1016/j.mrfmmm.2008.12.010

Cited by 74 publications

(63 citation statements)

References 24 publications

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“…21,22) Thus, AKR1C3 is suggested to play a key role in controlling proliferation and differentiation of the hormone-sensitive cancers and leukemia cells.…”

Section: )mentioning

confidence: 99%

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9,10-Phenanthrenequinone Induces Monocytic Differentiation of U937 Cells through Regulating Expression of Aldo-Keto Reductase 1C3

Matsunaga

Hosogai

Arakaki

et al. 2012

Biological & Pharmaceutical Bulletin

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Persistent inhalation of diesel exhaust particles results in damaged lung cells through formation of reactive oxygen species (ROS), but the details of the toxicity mechanism against monocytes are poorly understood. In this study, we used human promyelomonocytic U937 cells as surrogates of monocytes and investigated the toxicity mechanism initiated by exposure to 9,10-phenanthrenequinone (9,10-PQ), a major quinone component in diesel exhaust particles. A 24-h incubation with 9,10-PQ provoked apoptotic cell death, which was due to signaling through the enhanced ROS generation and concomitant caspase activation. Flow cytometric analyses of U937 cells after long-term exposure to 9,10-PQ revealed induction of differentiation that was evidenced by increasing expression of CD11b/CD18, a cell-surface marker for monocytic differentiation into macrophages. The 9,10-PQ-induced differentiation was significantly abolished by ROS inhibitors, suggesting that ROS generation contributes to cell differentiation. The 9,10-PQ treatment increased the expression of aldo-keto reductase (AKR) 1C3, which reached a peak at 1 to 2 d post-treatment and then declined. The bell-shaped curve of the AKR1C3 expression by 9,10-PQ resembled that caused by phorbol 12-myristate 13-acetate, a differentiation inducer. Additionally, the concomitant treatment with tolfenamic acid, a selective AKR1C3 inhibitor, sensitized the differentiation induced by 9,10-PQ. These results suggest that ROS formation during 9,10-PQ treatment acutely leads to apoptosis of U937 cells and the initiation of monocytic differentiation, which proceeds after the provisional overexpression of AKR1C3.Key words 9,10-phenanthrenequinone; differentiation; aldo-keto reductase 1C3; U937; oxidative stress Diesel exhaust particles (DEP) are believed to be harmful air pollutants that cause significant impediments to respiratory function leading to asthma and carcinogenesis.1,2) The mechanisms underlying their disorders is very complicated due to the involvement of a variety of lung cells such as epithelial cells, macrophages and lymphocytes.2) In the acute phase, macrophages are directly activated in response to stimulation with DEP resulting in the regulation of the immune signaling networks through secretion of pro-inflammatory mediators, cytokines 3) and chemokines. 4) In addition, the inhalation of DEP was shown to increase the number of lung macrophages, 5) which may be involved in clearing the particles by phagocytotic ingestion. 6) Thus, macrophages are believed to play pivotal roles in the cytoprotective responses against DEP. On the other hand, several researchers found that the administration of DEP lowers both antimicrobial and mitochondrial functions in alveolar macrophages through generation of reactive oxygen species (ROS) in addition to activating apoptotic signaling. 7,8) DEP are heterogeneous species that consist of a variety of organic and inorganic chemicals, such as polycyclic aromatic hydrocarbons, nitroaromatic hydrocarbons, heterocycles, aldehydes and quinones. 9)...

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“…21,22) Thus, AKR1C3 is suggested to play a key role in controlling proliferation and differentiation of the hormone-sensitive cancers and leukemia cells.…”

Section: )mentioning

confidence: 99%

“…19) In addition, down-regulation of AKR1C3 promotes differentiation of HL-60 and K562 leukemia cells. 21,22) Thus, AKR1C3 is suggested to play a key role in controlling proliferation and differentiation of the hormone-sensitive cancers and leukemia cells.…”

mentioning

confidence: 99%

9,10-Phenanthrenequinone Induces Monocytic Differentiation of U937 Cells through Regulating Expression of Aldo-Keto Reductase 1C3

Matsunaga

Hosogai

Arakaki

et al. 2012

Biological & Pharmaceutical Bulletin

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“…Treatment of HL-60 cells with the AKR inhibitors indomethacin or medroxyprogesterone acetate enhances both neutrophil and monocyte differentiation (7,8), and reciprocally, overexpression of AKR1C3 suppresses HL-60 differentiation (8,9). More recently, we have shown that knockdown of AKR1C3 in K562 cells results in erythroid differentiation (10). We have therefore proposed AKR1C3 as a novel regulator of myeloid cell differentiation and a potential new therapeutic target in leukemia.…”

Section: Introductionmentioning

confidence: 99%

AKR1C Isoforms Represent a Novel Cellular Target for Jasmonates alongside Their Mitochondrial-Mediated Effects

et al. 2009

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Members of the aldo-keto reductase (AKR) superfamily, particularly the AKR1C subfamily, are emerging as important mediators of the pathology of cancer. Agents that inhibit these enzymes may provide novel agents for either the chemoprevention or treatment of diverse malignancies. Recently, jasmonates, a family of plant stress hormones that bear a structural resemblance to prostaglandins, have been shown to elicit anticancer activities both in vitro and in vivo. In this study, we show that jasmonic acid (JA) and methyl jasmonate (MeJ) are capable of inhibiting all four human AKR1C isoforms. Although JA is the more potent inhibitor of recombinant AKR1C proteins, including the in vitro prostaglandin F synthase activity of AKR1C3, MeJ displayed greater potency in cellular systems that was, at least in part, due to increased cellular uptake of MeJ. Moreover, using the acute myelogenous leukemia cell lines HL-60 and KG1a, we found that although both jasmonates were able to induce high levels of reactive oxygen species in a dose-dependent fashion, only MeJ was able to induce high levels of mitochondrial superoxide (MSO), possibly as an epiphenomenon of mitochondrial damage. There was a strong correlation observed between MSO formation at 24 hours and reduced cellularity at day 5. In conclusion, we have identified AKR1C isoforms as a novel target of jasmonates in cancer cells and provide further evidence of the promise of these compounds, or derivatives thereof, as adjunctive therapies in the treatment of cancer.

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“…However, PR-104 showed promising activity with 6 of 17 AML patients treated with doses above 3 g/m 2 showing clinical responses. 19,30 Although biomarker data were limited in this study, AML blasts have been shown to have high levels of AKR1C3, 28 so that AKRIC3 may be a valuable biomarker in all acute leukemias.…”

Section: Primary T-all Mononuclear Cells Are More Sensitive To Pr-104mentioning

confidence: 93%

“…23 However, recent studies have shown that AKR1C3 is overexpressed in a number of human cancers including breast, 24,25 prostate, 26,27 and leukemia. [28][29][30] AKR1C3-mediated prostaglandin D2 metabolism has been shown to regulate myeloid 31 and erythroid 28 differentiation, suggesting that AKR1C3 represents a novel target for the treatment of AML 31 and chronic myelogenous leukemia. 28 Taken together, it is proposed that PR-104 may be a targeted drug for cancers that either express high AKR1C3 or are hypoxic.…”

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confidence: 99%

AKR1C3 is a biomarker of sensitivity to PR-104 in preclinical models of T-cell acute lymphoblastic leukemia

Manesh

El-Hoss

Evans

et al. 2015

Blood

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The aldo-keto reductase AKR1C3 contributes to 7,12-dimethylbenz(a)anthracene-3,4-dihydrodiol mediated oxidative DNA damage in myeloid cells: Implications for leukemogenesis

Cited by 74 publications

References 24 publications

9,10-Phenanthrenequinone Induces Monocytic Differentiation of U937 Cells through Regulating Expression of Aldo-Keto Reductase 1C3

9,10-Phenanthrenequinone Induces Monocytic Differentiation of U937 Cells through Regulating Expression of Aldo-Keto Reductase 1C3

AKR1C Isoforms Represent a Novel Cellular Target for Jasmonates alongside Their Mitochondrial-Mediated Effects

AKR1C3 is a biomarker of sensitivity to PR-104 in preclinical models of T-cell acute lymphoblastic leukemia

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