Targeting CDK9 by wogonin and related natural flavones potentiates the anti-cancer efficacy of the Bcl-2 family inhibitor ABT-263

• Verfasst von: Polier, Gernot [VerfasserIn]
• Verfasst von: Giaisi, Marco [VerfasserIn]
• Verfasst von: Köhler, Rebecca [VerfasserIn]
• Verfasst von: Müller, Wolfgang W. [VerfasserIn]
• Verfasst von: Lutz, Christoph [VerfasserIn]
• Verfasst von: Buß, Eike Christian [VerfasserIn]
• Verfasst von: Krammer, Peter H. [VerfasserIn]
• Verfasst von: Li-Weber, Min [VerfasserIn]
• Titel: Targeting CDK9 by wogonin and related natural flavones potentiates the anti-cancer efficacy of the Bcl-2 family inhibitor ABT-263
• Verf.angabe: Gernot Polier, Marco Giaisi, Rebecca Köhler, Wolfgang W. Müller, Christoph Lutz, Eike C. Buss, Peter H. Krammer and Min Li‐Weber
• Jahr: 2015
• Jahr des Originals: 2014
• Umfang: 11 S.
• Fussnoten: Online 4 June 2014 ; Gesehen am 22.07.2020
• Titel Quelle: Enthalten in: International journal of cancer
• Ort Quelle: Bognor Regis : Wiley-Liss, 1966
• Jahr Quelle: 2015
• Band/Heft Quelle: 136(2015), 3, Seite 688-698
• ISSN Quelle: 1097-0215
• DOI: doi:10.1002/ijc.29009
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: ABT-263
• Sach-SW: anti-cancer therapy
• Sach-SW: flavones
• Sach-SW: Mcl-1
• Sach-SW: wogonin
• K10plus-PPN: 1725250047

Abstract

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.