Huanglian, A chinese herbal extract, inhibits cell growth by suppressing the expression of cyclin B1 and inhibiting CDC2 kinase activity in human cancer cells.
Huanglian is an herb that is widely used in China for the treatment of gastroenteritis. We elected to determine whether huanglian could inhibit tumor cell growth by modulating molecular events directly associated with the cell cycle. Huanglian inhibited tumor growth and colony formation of gastric, colon, and breast cancer cell lines in a time- and dose-dependent manner. Cell growth was completely inhibited after 3 days of continuous drug exposure to 10 microg/ml of herb. This degree of growth inhibition was significantly greater than that observed with berberine, the major constituent of the herb. The inhibition of cell growth by huanglian was associated with up to 8-fold suppression of cyclin B1 protein. This resulted in complete inhibition of cdc2 kinase activity and accumulation of cells in G(2). The mRNA expression of cyclin B1 was not changed after huanglian treatment. There was no change in the protein expression of cyclins A or E. Therefore, the effect of huanglian on inhibiting tumor growth seems to be mediated by the selective suppression of cyclin B1, which results in the inhibition of cdc2 kinase activity. Inhibition of cyclin dependent kinase (cdk) activity is emerging as an attractive target for cancer chemotherapy. Huanglian represents a class of agents that can inhibit tumor cell growth by directly suppressing the expression of a cyclin subunit that is critical for cell cycle progression. These results indicate that traditional Chinese herbs may represent a new source of agents designed for selective inhibition of cyclin dependent kinases in cancer therapy.
Li
X K
XK
Gastrointestinal Oncology Research Laboratory for New Drug Development, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Motwani
M
M
Tong
W
W
Bornmann
W
W
Schwartz
G K
GK
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001599:Berberine / Q000494:pharmacology; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003114:Colony-Forming Units Assay; D019925:Cyclin A / Q000096:biosynthesis; D019926:Cyclin B / Q000096:biosynthesis / Q000235:genetics*; D056744:Cyclin B1; D019927:Cyclin E / Q000096:biosynthesis; D004365:Drugs, Chinese Herbal / Q000032:analysis / Q000494:pharmacology*; D016195:G2 Phase / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D008938:Mitosis / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; C534699:CCNB1 protein, human; D019925:Cyclin A; D019926:Cyclin B; D056744:Cyclin B1; D019927:Cyclin E; D004365:Drugs, Chinese Herbal; D012333:RNA, Messenger; D001599:Berberine; D016203:CDC2 Protein Kinase