Stereospecific reduction of a potent kinesin spindle protein (KSP) inhibitor in human tissues

Li, Chunze; Lu, Bing; Garbaccio, R. M.; Tasber, Edward S.; Fraley, Mark E.; Hartman, George D.; Ye, Jingjing; Harrelson, Jane Croft; Prueksaritanont, Thomayant

doi:10.1016/j.bcp.2010.01.024

Cited by 3 publications

(3 citation statements)

References 25 publications

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“…Although diflunisal was a potent inhibitor of AKR-mediated formation of M28, CYP3A4-mediated oxidative metabolites were unaltered, suggesting that diflunisal is not an inhibitor of CYP3A4. Recent reports showed that the AKR family of enzymes is involved in the metabolism of several drugs such as HIV integrase inhibitor S-1360 (Rosemond et al, 2004;Shimizu et al, 2007), kinesin spindle protein inhibitor (Li et al, 2010), the opiate antagonists naltrexone and naloxone, a serotonin (5-HT 3 ) receptor antagonist (dolaserton) (Breyer-Pfaff and Nill, 2004), the novel anticancer drug oracin (Wsol et al, 2007), the anticancer drug daunorubicin, antihypertensive drug befunolol, the diuretic drug ethacrynic acid, and loxoprofen (NSAID) (Wsol et al, 2007;Barski et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Characterization of Human Liver Enzymes Involved in the Biotransformation of Boceprevir, a Hepatitis C Virus Protease Inhibitor

Ghosal¹,

Yuan²,

Tong³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Boceprevir (SCH 503034), a protease inhibitor, is under clinical development for the treatment of human hepatitis C virus infections. In human liver microsomes, formation of oxidative metabolites after incubations with [ 14 C]boceprevir was catalyzed by CYP3A4 and CYP3A5. In addition, the highest turnover was observed in recombinant CYP3A4 and CYP3A5. After a single radiolabeled dose to human, boceprevir was subjected to two distinct pathways, namely cytochrome P450-mediated oxidation and ketone reduction. Therefore, attempts were made to identify the enzymes responsible for the formation of carbonyl-reduced metabolites. Human liver S9 and cytosol converted ϳ28 and ϳ68% of boceprevir to M28, respectively, in the presence of an NADPHgenerating system. Screening of boceprevir with recombinant human aldo-keto reductases (AKRs) revealed that AKR1C2 and AKR1C3 exhibited catalytic activity with respect to the formation of M؉2 metabolites (M28 and M31). The formation of M28 was inhibited by 100

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Section: Discussionmentioning

confidence: 99%

Characterization of Human Liver Enzymes Involved in the Biotransformation of Boceprevir, a Hepatitis C Virus Protease Inhibitor

Ghosal¹,

Yuan²,

Tong³

et al. 2010

Drug Metab Dispos

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“…AKR1C1 (encoding Aldo-keto Reductase Family 1, Member C1) was the most up-regulated gene (5.5-fold), although members C2 and C3 (AKR1C2 and AKR1C3) were also up-regulated by 3.5-and 3.0-fold, respectively. Aldo-keto reductases are a major superfamily of NAD(P)H-dependent oxidoreductases and family C members AKR1C1-AKR1C4, sharing a high percentage of amino-acid sequence identity (from 84 to 98%), are involved in 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 19 progesterone, testosterone, prostaglandin, and xenobiotic ketones metabolism 31,32 . In addition, AKR1C members have been found to be up-regulated in many cancers 33 and be associated with therapy response 34 .…”

Section: Molecular Signature Of Oncogenic Ep300 Indicates a Major Rolmentioning

confidence: 99%

“…In order to assess the role of AKR1C1, AKR1C2 and AKR1C3 in drug resistance we used a pharmacological approach. FFA is a non-steroid antiinflammatory pan-AKR1C1-4 inhibitor 31 clinically used for a variety of rheumatic disorders 36 . For this we first performed drug sensitivity assays and determined that 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 20 FFA concentrations up to 50 µM were not highly toxic for HS578T cells and drug resistant derivatives (Fig.…”

Section: Oncogenic Ep300 Can Be Targeted With Ffamentioning

confidence: 99%

Oncogenic EP300 can be targeted with inhibitors of aldo-keto reductases

Mahmud

Asaduzzaman

Kumar

et al. 2019

Biochemical Pharmacology

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E-cadherin transcriptional activator EP300 is down-regulated in metaplastic breast carcinoma, a rare form of triple negative and E-cadherin-negative aggressive breast cancer with a poor clinical outcome. In order to shed light on the regulation of Ecadherin by EP300 in breast cancer we analyzed by immunohistochemistry 41 cases of invasive breast cancer with both E-cadherin high and E-cadherin low expression levels, together with 20 non-malignant breast tissues. EP300 and E-cadherin showed a positive correlation in both non-malignant and cancer cases and both markers together were better predictors of lymph node metastasis than E-cadherin alone. These data support a metastasis suppressor role for EP300 in breast cancer. However, some reports suggest an oncogenic role for EP300. We generated a breast cancer cell model to study E-cadherin-independent effects of EP300 by over-expressing of EP300 in HS578T cells which have E-cadherin promoter hypermethylated. In this cell system, EP300 led to up-regulation of mesenchymal (vimentin, Snail, Slug, Zeb1) and stemness (ALDH + and CD44 high /CD24 low ) markers, increases in migration, invasion, anchorage-independent growth and drug resistance. Genome-wide expression profiling identified aldo-keto reductases AKR1C1-3 as effectors of stemness and drug resistance, since their pharmacological inhibition with flufenamic acid restored both doxorubicin and paclitaxel sensitivity and diminished mammosphere formation. Thus, in cells with a permissive E-cadherin promoter, EP300 acts as a tumour / metastasis supressor by up-regulating E-cadherin expression, maintenance of the epithelial phenotype and avoidance of an epithelial-to-mesenchymal transition. In cells in which the E-cadherin promoter is hypermethylated, EP300 functions as an oncogene via upregulation of aldo-keto reductases. This offers the rationale of using current aldo-keto reductase inhibitors in breast cancer treatment.3

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Gene expression profiling for analysis acquired oxaliplatin resistant factors in human gastric carcinoma TSGH-S3 cells: The role of IL-6 signaling and Nrf2/AKR1C axis identification

Chen

Chu

Liu

et al. 2013

Biochemical Pharmacology

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Stereospecific reduction of a potent kinesin spindle protein (KSP) inhibitor in human tissues

Cited by 3 publications

References 25 publications

Characterization of Human Liver Enzymes Involved in the Biotransformation of Boceprevir, a Hepatitis C Virus Protease Inhibitor

Characterization of Human Liver Enzymes Involved in the Biotransformation of Boceprevir, a Hepatitis C Virus Protease Inhibitor

Oncogenic EP300 can be targeted with inhibitors of aldo-keto reductases

Gene expression profiling for analysis acquired oxaliplatin resistant factors in human gastric carcinoma TSGH-S3 cells: The role of IL-6 signaling and Nrf2/AKR1C axis identification

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