Carcinogenesis Advance Access published online on January 6, 2005
Carcinogenesis, doi:10.1093/carcin/bgi014
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1 Department of Pharmaceutical Sciences, School of Pharmacy, SahmYook University, Seoul, Korea
* To whom correspondence should be addressed. This study was carried out to assess the anticancer efficacy of linarin (LN), linarin acetate (LA) and acacetin (AC), the flavonoid compounds with same flavone ring structure but different substitution, against human prostate cancer (PCA) LNCaP and DU145 cells. LN was isolated and purified from Chrysanthemum zawadskii; LA was chemically synthesized from LN; and AC was obtained commercially. In each case, cells were treated with these agents at 25-100 µM doses for 24-72 h. LN and LA showed moderate cell growth inhibition with different time kinetics as compared to AC. LN caused upto 5-fold increase in cell death and LA enhanced cell death by upto 4-fold with the increase in treatment time in both cell lines. AC showed a time- as well as -dose-dependent stronger cell growth inhibition (20-70%) accompanied by cell death as compared to LN and LA in both the cell lines. LN or LA did not show any profound effect on cell cycle arrest except for a moderate G1 arrest, whereas, AC showed a stronger G1 and/or G2-M arrest depending on the doses and treatment times. G1 arrest was associated with an increase in Cip1/p21 and a decrease in CDK2, CDK4 and CDK6 protein levels. G2-M arrest was associated with a decrease in Cdc25C, Cdc2/p34 and cyclin B1, which were more prominent in LNCaP compared to DU145 cells. LN, LA and AC-induced cell death was associated with significant increase in apoptosis induction (up to 5-6 fold) accompanied by PARP cleavage. Overall, AC showed more potent anticancer efficacy among these three flavonoids, which was diminished when its flavone ring was modified by disaccharide rhamnose substitution at C7 (LN) or acetylation of this substituted group (LA). These findings for the first time revealed the structural determinants in anticancer efficacy and mechanisms of these three flavonoids against human PCA cells.
Received November 16, 2004
Revised December 20, 2004
Accepted December 21, 2004
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
Acacetin inhibits cell growth and cell cycle progression, and induces apoptosis in human prostate cancer cells: structure-activity relationship with linarin and linarin acetate
2 Department of Pharmaceutical Sciences, School of Pharmacy, SahmYook University, Seoul, Korea; Department of Pharmacy, SahmYook University, Seoul, Korea
3 Department of Pharmaceutical Sciences, School of Pharmacy, SahmYook University, Seoul, Korea; University of Colorado Cancer Center, University of Colorado Health Sciences Center, Denver, CO 80262, USA
Rajesh Agarwal, E-mail: Rajesh.Agarwal{at}UCHSC.edu
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