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Research Paper
DH334, a β-carboline Anti-Cancer Drug, Inhibits the CDK Activity of Budding Yeast
Yan Li, Fengshan Liang, Wei Jiang, Fusheng Yu, Rihui Cao, Qinghe Ma, Xiuyong Dai, Jiandong Jiang, Yanchang Wang and Shuyi Si
volume 6 | issue 8
August 2007Pages: 1193 - 1199
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The β-carboline alkaloids present in medicinal plants, such as Peganum harmala and Eurycoma longifolia, have recently drawn attention due to their antitumor activities. Further mechanistic studies indicate that β-carboline derivatives inhibit DNA topoisomerases and interfere with DNA synthesis. Moreover, some β-carboline compounds are specific inhibitors of cyclin dependent kinases (CDKs). In this study we used budding yeast as a model system to investigate the antitumor mechanism of β-carboline drugs. We found that DH334, a β-carboline derivative, inhibits the growth of budding yeast. Strikingly, deletion of SIC1, which encodes the budding yeast CDK inhibitor, results in resistance to DH334. In contrast, yeast cells defective for Sic1 degradation exhibit more pronounced sensitivity to DH334. The presence of DH334 causes accumulation of yeast cells in G1 phase, indicating that DH334 blocks cell cycle initiation. We further demonstrated that DH334 inhibits CDK activity as indicated by the decreased phosphorylation of a CDK substrate. All these data suggest that the inhibition of CDK contributes to the toxicity of β-carboline derivatives to budding yeast. DH334 also inhibits the kinase activity of Cdk2/CyclinA in vitro. Therefore, we speculate that the antitumor activity of β-carboline drugs could be attributable to their inhibition of CDK.
Authors
Yan Li
Sichuan University
Fengshan Liang
College of Medicine, Florida State University, Tallahassee, Florida USA
Wei Jiang
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing, P.R. China
Fusheng Yu
Xinjiang Huashidan Pharmaceutical Co., P.R. China
Rihui Cao
Xinjiang Huashidan Pharmaceutical Co., P.R. China
Qinghe Ma
Xinjiang Huashidan Pharmaceutical Co., P.R. China
Xiuyong Dai
Xinjiang Huashidan Pharmaceutical Co., P.R. China
Jiandong Jiang
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing, P.R. China
Yanchang Wang
Florida State University, Tallahassee, FL
Shuyi Si
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing, P.R. China
We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link:
Download PDFIf the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.