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

Abstract

Tumor initiation, progression and resistance to therapies are tightly associated with over-expression of anti-apoptotic proteins Bcl-2, Bcl-x(L), 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-x(L), 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-x(L) 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.

• Authors: Gernot Polier, Marco Giaisi, Rebecca Köhler, Wolfgang W Müller, Christoph Lutz, Eike C Buss, Peter H Krammer, Min Li-Weber
• Journal: International journal of cancer (Int J Cancer) Vol. 136 Issue 3 Pg. 688-98 (Feb 01 2015) ISSN: 1097-0215 [Electronic] United States
• PMID: 24895203 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 UICC.

Chemical References

• Aniline Compounds
• Antineoplastic Agents
• Flavanones
• Flavones
• Sulfonamides
• Cyclin-Dependent Kinase 9
• wogonin
• navitoclax

Topics

• Aniline Compounds (pharmacology)
• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cyclin-Dependent Kinase 9 (antagonists & inhibitors)
• Drug Resistance, Neoplasm
• Drug Synergism
• Flavanones (pharmacology)
• Flavones (pharmacology)
• Humans
• Mice
• Sulfonamides (pharmacology)
• Xenograft Model Antitumor Assays