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Tetrandrine Induces Early G₁ Arrest in Human Colon Carcinoma Cells by Down-Regulating the Activity and Inducing the Degradation of G₁-S–Specific Cyclin-Dependent Kinases and by Inducing p53 and p21^Cip1

¹ Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland; and ² Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Tetrandrine is an antitumor alkaloid isolated from the root of Stephania tetrandra. We find that micromolar concentrations of tetrandrine irreversibly inhibit the proliferation of human colon carcinoma cells in MTT and clonogenic assays by arresting cells in G₁. Tetrandrine induces G₁ arrest before the restriction point in nocodazole- and serum-starved synchronized HT29 cells, without affecting the G₁-S transition in aphidicolin-synchronized cells. Tetrandrine-induced G₁ arrest is followed by apoptosis as shown by fluorescence-activated cell sorting, terminal deoxynucleotidyl transferase–mediated nick end labeling, and annexin V staining assays. Tetrandrine-induced early G₁ arrest is mediated by at least three different mechanisms. First, tetrandrine inhibits purified cyclin-dependent kinase 2 (CDK2)/cyclin E and CDK4 without affecting significantly CDK2/cyclin A, CDK1/cyclin B, and CDK6. Second, tetrandrine induces the proteasome-dependent degradation of CDK4, CDK6, cyclin D1, and E2F1. Third, tetrandrine increases the expression of p53 and p21^Cip1 in wild-type p53 HCT116 cells. Collectively, these results show that tetrandrine arrests cells in G₁ by convergent mechanisms, including down-regulation of E2F1 and up-regulation of p53/p21^Cip1.

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