Targeting CDK9 by wogonin and related natural flavones potentiates the anti-cancer efficacy of the Bcl-2 family inhibitor ABT-263
Tumor initiation, progression and resistance to therapies are tightly associated with over-expression of anti-apoptotic proteins Bcl-2, Bcl-xL, Bcl-w and Mcl-1. ABT-263 (Navitoclax), an orally bio-available small-molecule mimetic of the Bcl-2 homology domain 3, inhibits Bcl-2, Bcl-xL, and Bcl-w and...
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| Hauptverfasser: | , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
2015
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| In: |
International journal of cancer
Year: 2014, Jahrgang: 136, Heft: 3, Pages: 688-698 |
| ISSN: | 1097-0215 |
| DOI: | 10.1002/ijc.29009 |
| Online-Zugang: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1002/ijc.29009 Verlag, lizenzpflichtig, Volltext: https://onlinelibrary.wiley.com/doi/abs/10.1002/ijc.29009 
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| Verfasserangaben: | Gernot Polier, Marco Giaisi, Rebecca Köhler, Wolfgang W. Müller, Christoph Lutz, Eike C. Buss, Peter H. Krammer and Min Li‐Weber |
MARC
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| 245 | 1 | 0 | |a Targeting CDK9 by wogonin and related natural flavones potentiates the anti-cancer efficacy of the Bcl-2 family inhibitor ABT-263 |c Gernot Polier, Marco Giaisi, Rebecca Köhler, Wolfgang W. Müller, Christoph Lutz, Eike C. Buss, Peter H. Krammer and Min Li‐Weber |
| 246 | 3 | 3 | |a Targeting CDK nine by wogonin and related natural flavones potentiates the anti-cancer efficacy of the Bcl-two family inhibitor ABT-two hundred sixty-three |
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| 520 | |a Tumor initiation, progression and resistance to therapies are tightly associated with over-expression of anti-apoptotic proteins Bcl-2, Bcl-xL, Bcl-w and Mcl-1. ABT-263 (Navitoclax), an orally bio-available small-molecule mimetic of the Bcl-2 homology domain 3, inhibits Bcl-2, Bcl-xL, and Bcl-w and has shown anti-cancer effects mainly on lymphomas and lymphocytic leukemia. Despite promising results obtained from the clinical trials, the use of ABT-263 in patients is dose-limited due to causing thrombocytopenia via inhibition of Bcl-xL in platelets. ABT-199 specifically inhibits Bcl-2; however, its use is limited to tumors over-expressing only Bcl-2. Besides, many tumors resist treatment due to high levels of Mcl-1 expression or develop resistance via up-regulation of Mcl-1 during long-term exposure. These obstacles highlight the demand to improve the ABT-263-based therapy. In this study, we show that anti-cancer flavones, e.g., wogonin, baicalein, apigenin, chrysin and luteolin enhance ABT-263-induced apoptosis in different cancer cell lines and in primary AML and ALL cells by down-regulation of Mcl-1 expression. Importantly, wogonin does not enhance the toxicity of ABT-263 to proliferating normal T cells and thrombocytes. Wogonin also potentiates the lethality of ABT-263 in cancer cells which have acquired resistance to ABT-263. Furthermore, we show that combination of wogonin with ABT-263 promotes in vivo tumor regression in a human T-cell leukemia xenograft mouse model. Our study demonstrates that wogonin (and related flavones) reduce the effective dose of ABT-263 thereby possibly decreasing the risk of adverse side effects. | ||
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| 650 | 4 | |a ABT-263 | |
| 650 | 4 | |a anti-cancer therapy | |
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| 650 | 4 | |a Mcl-1 | |
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