A highly specific aldose reductase inhibitor, ethyl 1-benzyl-3-hydroxy-2(5H)-oxopyrrole-4-carboxylate and its congeners

Mylari, Banavara L.; Beyer, Thomas A.; Siegel, Todd W.

doi:10.1021/jm00107a020

Cited by 53 publications

(35 citation statements)

References 3 publications

(4 reference statements)

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“…Published studies have demonstrated that the carboxylic class of AR inhibitors, such as zopolrestat, is 200 fold more selective for AR over aldehyde reductase. 30 Hence, at the concentrations used in this study, the inhibition of aldehyde reductase is unlikely to have played any part in the lesion size reduction in diabetic mice.…”

Section: Discussionmentioning

confidence: 76%

Human Aldose Reductase Expression Accelerates Atherosclerosis in Diabetic Apolipoprotein E−/− Mice

Vedantham

Noh

Ananthakrishnan

et al. 2011

ATVB

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Objective There are several pathways that mediate the aberrant metabolism of glucose and that might induce greater vascular damage in the setting of diabetes. The polyol pathway mediated by aldose reductase (AR) has been postulated to be one such pathway. However, it has been reported that AR reduces toxic lipid aldehydes and, under some circumstances, might be anti-atherogenic. Methods and Results Atherosclerosis development was quantified in two lines of transgenic mice expressing human AR (hAR) crossed on the apoE knockout (apoE−/−) background. The transgenes were used to increase the normally low levels of this enzyme in wild type mice. Both generalized hAR overexpression and hAR expression via the Tie 2 promoter increased lesion size in streptozotocin (STZ) diabetic mice. In addition, pharmacologic inhibition of AR reduced lesion size. Conclusion Although in some settings AR expression might reduce levels of toxic aldehydes, transgenic expression of this enzyme within the artery wall leads to greater atherosclerosis.

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Section: Discussionmentioning

confidence: 76%

Human Aldose Reductase Expression Accelerates Atherosclerosis in Diabetic Apolipoprotein E−/− Mice

Vedantham

Noh

Ananthakrishnan

et al. 2011

ATVB

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“…We next assessed the role of aldose and aldehyde reductases, members of a superfamily of aldoketo reductases that were also considered to form anthracycline secondary alcohol metabolites (Felsted et al, 1974;Behnia and Boroujerdi, 1999). The role of these enzymes was probed with EBPC (specific inhibitor of aldose reductases) (Mylari et al, 1991), tolrestat (mixed inhibitor of aldose and aldehyde reductases) (Barski et al, 1996), and AL1576 (specific inhibitor of aldehyde reductases) (Barski et al, 1995(Barski et al, , 1996. EBPC exhibited a very high IC 50 value (ϳ1 mM), whereas tolrestat and AL1576 exhibited IC 50 values of 30 M or 5 M, respectively (see also Fig.…”

Section: Doxorubicinol Formation In Human Heartmentioning

confidence: 99%

Paclitaxel and Docetaxel Stimulation of Doxorubicinol Formation in the Human Heart: Implications for Cardiotoxicity of Doxorubicin-Taxane Chemotherapies

Salvatorelli

Menna

Cascegna

et al. 2006

J Pharmacol Exp Ther

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Antitumor therapy with the anthracycline doxorubicin is limited by a dose-related cardiotoxicity that is aggravated by a concomitant administration of the taxane paclitaxel. Previous limited studies with isolated human heart cytosol showed that paclitaxel was able to stimulate an NADPH-dependent reduction of doxorubicin to its toxic secondary alcohol metabolite doxorubicinol. Here we characterized that 0.25 to 2.5 M paclitaxel caused allosteric effects that increased doxorubicinol formation in human heart cytosol, whereas 5 to 10 M paclitaxel decreased doxorubicinol formation. The closely related taxane docetaxel caused similar effects. Basal or taxane-stimulated doxorubicinol formation was blunted by 2,7-difluorospirofluorene-9,5Ј-imidazolidine-2Ј,4Ј-dione (AL1576), a specific inhibitor of aldehyde reductases. Doxorubicinol was measured also in the cytosol of human myocardial strips incubated in plasma and exposed to doxorubicin in the absence or presence of paclitaxel or docetaxel and their clinical vehicles Cremophor EL or polysorbate 80. Low concentrations of taxanes stimulated doxorubicinol formation, whereas high concentrations decreased it. Doxorubicinol formation reached its maximum on adding plasma with 6 M paclitaxel or docetaxel; this corresponded to the partitioning of 1.5 to 2.5 M taxanes in the cytosol of the strips. Taxane-stimulated doxorubicinol formation was not mediated by vehicles, nor was it caused by increased doxorubicin uptake or de novo protein synthesis; however, doxorubicinol formation was blunted by AL1576. These results show that allosteric interactions with cytoplasmic aldehyde reductases enable paclitaxel or docetaxel to stimulate doxorubicinol formation in human heart. This information serves metabolic insights into the risk of cardiotoxicity induced by doxorubicin-taxane therapies.The anthracycline doxorubicin and the taxane paclitaxel are both highly active in breast cancer. Doxorubicin and paclitaxel exhibit different mechanisms of action (DNA intercalation and topoisomerase II inhibition versus microtubule stabilization), nonoverlapping toxicities (cardiomyopathy versus neuropathy), and incomplete cross-resistance;

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“…Experiments with laboratory animals or reconstituted biochemical systems showed that anthracycline secondary alcohol metabolites could be formed by an array of carbonyl-and aldehyde-or aldose-reductases, whereas experiments with human myocardium showed that doxorubicinol was formed primarily by aldehyde reductases (Slupe et al, 2005;Salvatorelli et al, 2006b). To characterize the enzymology of epirubicinol formation versus doxorubicinol formation, we treated the isolated human heart cytosol with AL1576 (inhibitor of aldehyde reductases) (Barski et al, 1995), EBPC (inhibitor of aldose reductases) (Mylari et al, 1991), and quercetin (inhibitor of human carbonyl reductases) (Holleran et al, 2004). In incubations with anthracyclines at three times their K m values, AL1576 inhibited the formation of both doxorubicinolone and doxorubicinol or epirubicinol with IC 50 values Ͻ10 M, whereas quercetin or EBPC inhibited with IC 50 values that were at least 1 order of magnitude higher (Table 4).…”

Section: Tablementioning

confidence: 99%

Defective Taxane Stimulation of Epirubicinol Formation in the Human Heart: Insight into the Cardiac Tolerability of Epirubicin-Taxane Chemotherapies

Salvatorelli¹,

Menna²,

Gianni³

et al. 2006

J Pharmacol Exp Ther

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The antitumor anthracycline doxorubicin induces a dose-related cardiotoxicity that correlates with the myocardial levels of its secondary alcohol metabolite doxorubicinol. Combining doxorubicin with taxanes such as paclitaxel or docetaxel may aggravate cardiotoxicity, presumably because the taxanes cause an allosteric-like stimulation of cytoplasmic aldehyde reductases that convert doxorubicin to doxorubicinol in the heart. A less severe aggravation of cardiotoxicity was observed on combining taxanes with epirubicin, a closely related analog of doxorubicin; therefore, we characterized whether the cardiac tolerability of epirubicin-taxane therapies could be due to a defective taxane stimulation of the conversion of epirubicin to its secondary alcohol metabolite epirubicinol. Comparisons between doxorubicin and epirubicin in isolated human heart cytosol showed that epirubicin exhibited a lower V max /K m value for reaction with aldehyde reductases and a defective stimulation of epirubicinol formation by paclitaxel or docetaxel. A similar pattern occurred in the soluble fraction of human myocardial strips incubated in plasma with anthracyclines and paclitaxel or docetaxel, formulated in their clinical vehicles Cremophor EL or polysorbate 80. Doxorubicin, but not epirubicin, was also able to generate reactive oxygen species in the membrane fraction of myocardial strips; however, the levels of doxorubicin-derived reactive oxygen species were not further augmented by paclitaxel. These results support the notion that taxanes might aggravate the cardiotoxicity of doxorubicin through a specific stimulation of doxorubicinol formation. The failure of paclitaxel or docetaxel to stimulate epirubicinol formation therefore uncovers an important determinant of the improved cardiac tolerability of epirubicin-taxane combinations.The anthracycline doxorubicin and the taxanes paclitaxel or docetaxel are highly active antitumor drugs. Doxorubicinpaclitaxel combinations were shown to induce high response rates in women with metastatic breast cancer, particularly when the two drugs were administered almost concomitantly; unfortunately, however, the clinical use of doxorubicinpaclitaxel combinations was limited by a higher than expected incidence of the cardiac toxicity known to be induced by doxorubicin. For example, doxorubicin immediately followed by paclitaxel caused congestive heart failure (CHF) at a cumulative dose of 420 to 480 mg of doxorubicin/m 2 , which was below a safety limit usually set at ϳ500 to 550 mg of doxorubicin/m 2 (Gianni et al., 1995). Paclitaxel alone had not been reported to induce CHF; therefore, the unexpected cardiotoxicity of doxorubicin-paclitaxel uncovered a cardiotoxic synergism between the anthracycline and the taxane and prompted studies that identified 360 mg of doxorubicin/m 2 as the highest cumulative dose of anthracycline, which could be safely administered in combination with paclitaxel (Perotti et al., 2003).A higher than expected incidence of cardiotoxicity was not observed in metastat...

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A highly specific aldose reductase inhibitor, ethyl 1-benzyl-3-hydroxy-2(5H)-oxopyrrole-4-carboxylate and its congeners

Cited by 53 publications

References 3 publications

Human Aldose Reductase Expression Accelerates Atherosclerosis in Diabetic Apolipoprotein E−/− Mice

Human Aldose Reductase Expression Accelerates Atherosclerosis in Diabetic Apolipoprotein E−/− Mice

Paclitaxel and Docetaxel Stimulation of Doxorubicinol Formation in the Human Heart: Implications for Cardiotoxicity of Doxorubicin-Taxane Chemotherapies

Defective Taxane Stimulation of Epirubicinol Formation in the Human Heart: Insight into the Cardiac Tolerability of Epirubicin-Taxane Chemotherapies

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