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Identification of hematein as a novel inhibitor of protein kinase CK2 from a natural product library.

Hung MS, Xu Z, Lin YC, Mao JH, Yang CT, Chang PJ, Jablons DM, You L - BMC Cancer (2009)

Bottom Line: Hematein was identified as a novel CK2 inhibitor that is highly selective among a panel of kinases.In this study, we showed that hematein is a novel selective and cell permeable small molecule CK2 inhibitor.This compound may represent a promising class of CK2 inhibitors.

View Article: PubMed Central - HTML - PubMed

Affiliation: Thoracic Oncology Laboratory, Department of Surgery, Comprehensive Cancer Center, University of California, San Francisco, CA 94115, USA. Ming-Szu.Hung@ucsfmedctr.org

ABSTRACT

Background: Casein kinase 2 (CK2) is dysregulated in various human cancers and is a promising target for cancer therapy. To date, there is no small molecular CK2 inhibitor in clinical trial yet. With the aim to identify novel CK2 inhibitors, we screened a natural product library.

Methods: We adopted cell-based proliferation and CK2 kinase assays to screen CK2 inhibitors from a natural compound library. Dose-dependent response of CK2 inhibitors in vitro was determined by a radioisotope kinase assay. Western blot analysis was used to evaluate down stream Akt phosphorylation and apoptosis. Apoptosis was also evaluated by annexin-V/propidium iodide (PI) labeling method using flow cytometry. Inhibition effects of CK2 inhibitors on the growth of cancer and normal cells were evaluated by cell proliferation and viability assays.

Results: Hematein was identified as a novel CK2 inhibitor that is highly selective among a panel of kinases. It appears to be an ATP non-competitive and partially reversible CK2 inhibitor with an IC50 value of 0.55 muM. In addition, hematein inhibited cancer cell growth partially through down-regulation of Akt phosphorylation and induced apoptosis in these cells. Furthermore, hematein exerted stronger inhibition effects on the growth of cancer cells than in normal cells.

Conclusion: In this study, we showed that hematein is a novel selective and cell permeable small molecule CK2 inhibitor. Hematein showed stronger growth inhibition effects to cancer cells when compared to normal cells. This compound may represent a promising class of CK2 inhibitors.

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Validation of inhibition effects of selected compounds on CK2 kinase activity and structures of compounds. A. Inhibition effects of selected compounds on CK2 kinase activity was validated by radioisotope kinase assay at a concentration of 10 μM compound using 10 μM ATP. TBB is the positive control. Ck2 kinase activity is represented as relative CK2 activity to controls (DMSO). Data represents the average of duplicate experiments and bars indicate SD.4A3: hematein. B. Structure of compounds: 4A3 (hematein): 3, 4, 10, 6a-tetrahydroxy-7, 6a-dihydroindeno [2, 1-c] chroman-9-one MW 300.26, CAS No. 15489-90-4; 4A6: 5-methoxyfurano [3,2-g]chromen-2-one; 4A9: 4-hydroxy-3-{2- [8-hydroxy-7-(hydroxymethyl)-1,7-dimethyl-3-methylenebicyclo[4. 4.0]dec-2-yl]ethylidene}-4,5-dihydrofuran-2-one.
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Figure 2: Validation of inhibition effects of selected compounds on CK2 kinase activity and structures of compounds. A. Inhibition effects of selected compounds on CK2 kinase activity was validated by radioisotope kinase assay at a concentration of 10 μM compound using 10 μM ATP. TBB is the positive control. Ck2 kinase activity is represented as relative CK2 activity to controls (DMSO). Data represents the average of duplicate experiments and bars indicate SD.4A3: hematein. B. Structure of compounds: 4A3 (hematein): 3, 4, 10, 6a-tetrahydroxy-7, 6a-dihydroindeno [2, 1-c] chroman-9-one MW 300.26, CAS No. 15489-90-4; 4A6: 5-methoxyfurano [3,2-g]chromen-2-one; 4A9: 4-hydroxy-3-{2- [8-hydroxy-7-(hydroxymethyl)-1,7-dimethyl-3-methylenebicyclo[4. 4.0]dec-2-yl]ethylidene}-4,5-dihydrofuran-2-one.

Mentions: Third, the inhibition effects of selected compounds were further validated by radioisotope CK2 kinase assay at 10 μM ATP and similar results were noted (Fig. 2A). The 4A3 compound is hematein (3, 4, 10, 6a-tetrahydroxy-7, 6a-dihydroindeno [2, 1-c] chroman-9-one) (Fig 2B).


Identification of hematein as a novel inhibitor of protein kinase CK2 from a natural product library.

Hung MS, Xu Z, Lin YC, Mao JH, Yang CT, Chang PJ, Jablons DM, You L - BMC Cancer (2009)

Validation of inhibition effects of selected compounds on CK2 kinase activity and structures of compounds. A. Inhibition effects of selected compounds on CK2 kinase activity was validated by radioisotope kinase assay at a concentration of 10 μM compound using 10 μM ATP. TBB is the positive control. Ck2 kinase activity is represented as relative CK2 activity to controls (DMSO). Data represents the average of duplicate experiments and bars indicate SD.4A3: hematein. B. Structure of compounds: 4A3 (hematein): 3, 4, 10, 6a-tetrahydroxy-7, 6a-dihydroindeno [2, 1-c] chroman-9-one MW 300.26, CAS No. 15489-90-4; 4A6: 5-methoxyfurano [3,2-g]chromen-2-one; 4A9: 4-hydroxy-3-{2- [8-hydroxy-7-(hydroxymethyl)-1,7-dimethyl-3-methylenebicyclo[4. 4.0]dec-2-yl]ethylidene}-4,5-dihydrofuran-2-one.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2696466&req=5

Figure 2: Validation of inhibition effects of selected compounds on CK2 kinase activity and structures of compounds. A. Inhibition effects of selected compounds on CK2 kinase activity was validated by radioisotope kinase assay at a concentration of 10 μM compound using 10 μM ATP. TBB is the positive control. Ck2 kinase activity is represented as relative CK2 activity to controls (DMSO). Data represents the average of duplicate experiments and bars indicate SD.4A3: hematein. B. Structure of compounds: 4A3 (hematein): 3, 4, 10, 6a-tetrahydroxy-7, 6a-dihydroindeno [2, 1-c] chroman-9-one MW 300.26, CAS No. 15489-90-4; 4A6: 5-methoxyfurano [3,2-g]chromen-2-one; 4A9: 4-hydroxy-3-{2- [8-hydroxy-7-(hydroxymethyl)-1,7-dimethyl-3-methylenebicyclo[4. 4.0]dec-2-yl]ethylidene}-4,5-dihydrofuran-2-one.
Mentions: Third, the inhibition effects of selected compounds were further validated by radioisotope CK2 kinase assay at 10 μM ATP and similar results were noted (Fig. 2A). The 4A3 compound is hematein (3, 4, 10, 6a-tetrahydroxy-7, 6a-dihydroindeno [2, 1-c] chroman-9-one) (Fig 2B).

Bottom Line: Hematein was identified as a novel CK2 inhibitor that is highly selective among a panel of kinases.In this study, we showed that hematein is a novel selective and cell permeable small molecule CK2 inhibitor.This compound may represent a promising class of CK2 inhibitors.

View Article: PubMed Central - HTML - PubMed

Affiliation: Thoracic Oncology Laboratory, Department of Surgery, Comprehensive Cancer Center, University of California, San Francisco, CA 94115, USA. Ming-Szu.Hung@ucsfmedctr.org

ABSTRACT

Background: Casein kinase 2 (CK2) is dysregulated in various human cancers and is a promising target for cancer therapy. To date, there is no small molecular CK2 inhibitor in clinical trial yet. With the aim to identify novel CK2 inhibitors, we screened a natural product library.

Methods: We adopted cell-based proliferation and CK2 kinase assays to screen CK2 inhibitors from a natural compound library. Dose-dependent response of CK2 inhibitors in vitro was determined by a radioisotope kinase assay. Western blot analysis was used to evaluate down stream Akt phosphorylation and apoptosis. Apoptosis was also evaluated by annexin-V/propidium iodide (PI) labeling method using flow cytometry. Inhibition effects of CK2 inhibitors on the growth of cancer and normal cells were evaluated by cell proliferation and viability assays.

Results: Hematein was identified as a novel CK2 inhibitor that is highly selective among a panel of kinases. It appears to be an ATP non-competitive and partially reversible CK2 inhibitor with an IC50 value of 0.55 muM. In addition, hematein inhibited cancer cell growth partially through down-regulation of Akt phosphorylation and induced apoptosis in these cells. Furthermore, hematein exerted stronger inhibition effects on the growth of cancer cells than in normal cells.

Conclusion: In this study, we showed that hematein is a novel selective and cell permeable small molecule CK2 inhibitor. Hematein showed stronger growth inhibition effects to cancer cells when compared to normal cells. This compound may represent a promising class of CK2 inhibitors.

Show MeSH
Related in: MedlinePlus