DH334, a β-carboline anti-cancer drug, Inhibits the CDK activity of budding yeast

Abstract

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.