Wogonin and related natural flavones are inhibitors of CDK9 that induce apoptosis in cancer cells by transcriptional suppression of Mcl-1

Abstract

The wogonin-containing herb Scutellaria baicalensis has successfully been used for curing various diseases in traditional Chinese medicine. Wogonin has been shown to induce apoptosis in different cancer cells and to suppress growth of human cancer xenografts in vivo. However, its direct targets remain unknown. In this study, we demonstrate for the first time that wogonin and structurally related natural flavones, for example, apigenin, chrysin and luteolin, are inhibitors of cyclin-dependent kinase 9 (CDK9) and block phosphorylation of the carboxy-terminal domain of RNA polymerase II at Ser2. This effect leads to reduced RNA synthesis and subsequently rapid downregulation of the short-lived anti-apoptotic protein myeloid cell leukemia 1 (Mcl-1) resulting in apoptosis induction in cancer cells. We show that genetic inhibition of Mcl-1 or CDK9 expression by siRNA is sufficient to mimic flavone-induced apoptosis. Pull-down and in silico docking studies demonstrate that wogonin directly binds to CDK9, presumably to the ATP-binding pocket. In contrast, wogonin does not inhibit CDK2, CDK4 and CDK6 at doses that inhibit CDK9 activity. Furthermore, we show that wogonin preferentially inhibits CDK9 in malignant compared with normal lymphocytes. Thus, our study reveals a new mechanism of anti-cancer action of natural flavones and supports CDK9 as a therapeutic target in oncology.

Infiltrating Macrophages Are Key to the Development of Seizures following Virus Infection

“…Whether wogonin targets activated TMEV-specific T cells is not known; however, due to the low concentration of wogonin administered, a certain percentage of activated TMEV-specific T cells may escape targeting and be sufficient for viral clearance. These results are in agreement with previous reports that demonstrated wogonin specifically targeted activated cells and not resting immune cells (36,53). Therefore, wogonin-treated mice are able to clear TMEV, even though wogonin inhibits activated macrophages.…”

Combination of wogonin and sorafenib effectively kills human hepatocellular carcinoma cells through apoptosis potentiation and autophagy inhibition

“…Wogonin has been shown to have antioxidant, antiviral, antithrombotic and anti-inflammatory activities in both in vitro and in vivo studies (26)(27)(28)(29). The anticancer activity of wogonin is demonstrated by inducing apoptosis in cancer cells and suppressing growth of human cancer xenografts in vivo (30,31). Wogonin has also been tested to kill cancer cells in combination with other chemotherapeutics (32,33).…”

A Novel Herbal Formula Induces Cell Cycle Arrest and Apoptosis in Association With Suppressing the PI3K/AKT Pathway in Human Lung Cancer A549 Cells

“…Rigorous and systematic evaluations are, however, necessary to establish the efficacy of herbal formulas and transform traditional herbal practices into sciencebased medicines. [13][14][15][16][17] In the present article, we evaluated the anticancer activity of Ke formula, which has been shown to be effective in the clinic. The crude formula used in this study followed TCM treatment principles based on syndrome differentiation.…”