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Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is one of the most promising candidates for new cancer therapeutics. A current problem is that some cancers still remain resistant to TRAIL. We show for the first time that a naturally occurring flavonoid, baicalein, overcomes TRAIL resistance in cancer cells. The combination of baicalein and TRAIL effectively induced apoptosis in TRAIL-resistant colon cancer SW480 cells. Baicalein up-regulated the expression of death receptor 5 (DR5) among TRAIL receptors at the mRNA and protein levels. Suppression of this up-regulation with small interfering RNA (siRNA) efficiently reduced the apoptosis induced by TRAIL and baicalein, suggesting that the sensitization was mediated through DR5 induction. Moreover, baicalein also overcame TRAIL resistance with DR5 up-regulation in prostate cancer PC3 cells. Of note, the combination of TRAIL and baicalein hardly induced apoptosis in normal human cells, such as blood cells and hepatocytes. Baicalein increased DR5 promoter activity, and this enhanced activity was diminished by mutation of a CCAAT/enhancer-binding protein homologous protein (CHOP)-binding site in SW480 cells. In SW480 cells, CHOP siRNA blocked both functions of baicalein. CHOP expression was induced by baicalein in SW480 cells; however, in PC3 cells, baicalein scarcely induced CHOP and mutation of the CHOP-binding site did not abrogate the DR5 promoter activation by baicalein. Interestingly, baicalein induced reactive oxygen species (ROS) and a ROS scavenger prevented DR5 expression and TRAIL sensitization in PC3 but not SW480 cells. These results indicate that, using two different pathways, baicalein exposes cancer surveillance of TRAIL and overcomes TRAIL resistance in cancer cells.
Highlights
Baicalein is a flavonoid derived from the root of Scutellaria baicalensis, widely used in Chinese herbal medicine
To confirm that the apoptosis caused by the combination of baicalein and Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is mediated through death receptors, we used death receptor 5 (DR5)/Fc chimeric protein, which has a dominant-negative function against the TRAIL receptors
The DR5/Fc protein efficiently blocked apoptosis caused by TRAIL and baicalein in SW480 cells (Fig. 1C)
Summary
Baicalein is a flavonoid derived from the root of Scutellaria baicalensis, widely used in Chinese herbal medicine. Baicalein is known as a selective 12-lipoxygenase (12-LOX) inhibitor [1], which induces antiproliferation and apoptosis in various cancer. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Doi:10.1158/0008-5472.CAN-08-1120 cells [2,3,4]. This flavonoid has other activities, such as antibacterial, antiviral, antioxidative, and prooxidative effects [5, 6]. The molecular mechanism of the antitumor effect is still unclear. Reactive oxygen species (ROS) are critical signaling molecules and play important roles in a variety of normal biochemical functions and abnormal pathologic processes
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