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Carcinogenesis Advance Access published online on July 18, 2007
Carcinogenesis, doi:10.1093/carcin/bgm126
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
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Acteoside inhibits human promyelocytic HL-60 leukemia cell proliferation via inducing cell cycle arrest at G0/G1 phase and differentiation into monocyte

Kyung-Won Lee, HyoungJa Kim1, YongSup Lee, Hee-Jun Park2, Jong-Won Choi3, Joohun Ha4 and Kyung-Tae Lee*

College of Pharmacy, Kyung-Hee University, Hoegi-Dong, Seoul 130-701, Korea
1 Life Sciences Division, Korea Institute of Science and Technology P.O. Box 131, Seoul 130-650 Korea
2 Division of Applied Plant Sciences, Sang-Ji University, Woosan-Dong, Wonju 220-702, Korea
3 College of Pharmacy, Kyungsung University, Dayeon-Dong, Pusan, 608-736, Korea
4 College of Medicine, Kyung Hee University, Hoegi-Dong , Seoul 130-701, Korea

* To whom correspondence should be addressed, E-mail: ktlee{at}khu.ac.kr

We investigated the in vitro effects of acteoside on the proliferation, cell cycle regulation, and differentiation of HL-60 human promyelocytic leukemia cells. Acteoside inhibited the proliferation of HL-60 cells in a concentration- and time-dependent manner with an IC50, approximately 30 µM. DNA flow cytometric analysis indicated that acteoside blocked cell cycle progression at the G1 phase in HL-60 human promyelocytic leukemia cells. Among the G1 phase cell cycle-related proteins, the levels of CDK2, CDK6, cyclin D1, cyclin D2, cyclin D3, and cyclin E were reduced by acteoside, whereas the steady-state level of CDK4 was unaffected. The protein and mRNA levels of CDK inhibitors (CKIs), such as p21CIP1/WAF1 and p27KIP1, were gradually increased after acteoside treatment in a time-dependent manner. In addition, acteoside markedly enhanced the binding of p21CIP1/WAF1 and p27KIP1 to CDK4 and CDK6, resulting in the reduction of CDK2, CDK4 and CDK6 activities. Moreover, the hypophosphorylated form of Rb increased, leading to the enhanced binding of pRB and E2F1. Our results further suggest that acteoside is a potent inducer of differentiation of HL-60 cells, based on biochemical activities and the expression level of CD14 cell surface antigen. In conclusion, the onset of acteoside-induced G1 arrest of HL-60 cells prior to the differentiation appears to be tightly linked to up-regulation of the p21CIP1/WAF1 and p27KIP1 levels and decreases in the CDK2, CDK4 and CDK6 activities. These findings, for the first time, reveal the mechanism underlying the anti-proliferative effect of acteoside on human promyelocytic HL-60 cells.

Key Words: acteoside • cell cycle • differentiation • CDK • TGF-ß1

Received October 30, 2005; revised April 27, 2007; accepted May 17, 2007.


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