title: 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.affiliation: Tumorimmunology Program (D030), German Cancer Research Center (DKFZ), D-69120, Heidelberg, Germany.
authors.forename: Gernot
authors.initials: G
authors.lastname: Polier
authors.forename: Marco
authors.initials: M
authors.lastname: Giaisi
authors.forename: Rebecca
authors.initials: R
authors.lastname: Köhler
authors.forename: Wolfgang W
authors.initials: WW
authors.lastname: Müller
authors.forename: Christoph
authors.initials: C
authors.lastname: Lutz
authors.forename: Eike C
authors.initials: EC
authors.lastname: Buss
authors.forename: Peter H
authors.initials: PH
authors.lastname: Krammer
authors.forename: Min
authors.initials: M
authors.lastname: Li-Weber
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D042863:Cyclin-Dependent Kinase 9 / Q000037:antagonists & inhibitors*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D044950:Flavanones / Q000494:pharmacology*; D047309:Flavones / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D013449:Sulfonamides / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D044950:Flavanones; D047309:Flavones; D013449:Sulfonamides; D042863:Cyclin-Dependent Kinase 9; C085514:wogonin; C528561:navitoclax
keywords: ABT-263; Mcl-1; anti-cancer therapy; flavones; wogonin