A novel anticancer agent, decursin, induces G1 arrest and apoptosis in human prostate carcinoma cells.

Abstract

We isolated a coumarin compound decursin (C(19)H(20)O(5); molecular weight 328) from Korean angelica (Angelica gigas) root and characterized it by spectroscopy. Here, for the first time, we observed that decursin (25-100 micromol/L) treatment for 24 to 96 hours strongly inhibits growth and induces death in human prostate carcinoma DU145, PC-3, and LNCaP cells. Furthermore, we observed that decursinol [where (CH(3))(2)-C=CH-COO- side chain of decursin is substituted with -OH] has much lower effects compared with decursin, suggesting a possible structure-activity relationship. Decursin-induced growth inhibition was associated with a strong G(1) arrest (P < 0.001) in DU145 and LNCaP cells, and G(1), S as well as G(2)-M arrests depending upon doses and treatment times in PC-3 cells. Comparatively, decursin was nontoxic to human prostate epithelial PWR-1E cells and showed only moderate growth inhibition and G(1) arrest. Consistent with G(1) arrest in DU145 cells, decursin strongly increased protein levels of Cip1/p21 but showed a moderate increase in Kip1/p27 with a decrease in cyclin-dependent kinases (CDK); CDK2, CDK4, CDK6, and cyclin D1, and inhibited CDK2, CDK4, CDK6, cyclin D1, and cyclin E kinase activity, and increased binding of CDK inhibitor (CDKI) with CDK. Decursin-caused cell death was associated with an increase in apoptosis (P < 0.05-0.001) and cleaved caspase-9, caspase-3, and poly(ADP-ribose) polymerase; however, pretreatment with all-caspases inhibitor (z-VAD-fmk) only partially reversed decursin-induced apoptosis, suggesting the involvement of both caspase-dependent and caspase-independent pathways. These findings suggest the novel anticancer efficacy of decursin mediated via induction of cell cycle arrest and apoptosis selectively in human prostate carcinoma cells.

• Authors: Dongsool Yim, Rana P Singh, Chapla Agarwal, Sookyeon Lee, Hyungjoon Chi, Rajesh Agarwal
• Journal: Cancer research (Cancer Res) Vol. 65 Issue 3 Pg. 1035-44 (Feb 01 2005) ISSN: 0008-5472 [Print] United States
• PMID: 15705905 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Benzopyrans
• Butyrates
• CDKN1A protein, human
• CDKN1B protein, human
• Carrier Proteins
• Cell Cycle Proteins
• Cyclin-Dependent Kinase Inhibitor p21
• Intracellular Signaling Peptides and Proteins
• Protein Kinase Inhibitors
• Cyclin-Dependent Kinase Inhibitor p27
• decursin
• Cyclin-Dependent Kinases
• Caspases

Topics

• Apoptosis (drug effects)
• Benzopyrans (pharmacology)
• Butyrates (pharmacology)
• Carrier Proteins (biosynthesis, genetics)
• Caspases (metabolism)
• Cell Cycle Proteins (biosynthesis, genetics)
• Cell Growth Processes (drug effects)
• Cell Line, Tumor
• Cyclin-Dependent Kinase Inhibitor p21
• Cyclin-Dependent Kinase Inhibitor p27
• Cyclin-Dependent Kinases (antagonists & inhibitors)
• Enzyme Activation (drug effects)
• Epithelial Cells (drug effects)
• G1 Phase (drug effects)
• Humans
• Intracellular Signaling Peptides and Proteins (genetics)
• Male
• Nuclear Magnetic Resonance, Biomolecular
• Prostate (cytology, drug effects)
• Prostatic Neoplasms (drug therapy, genetics, metabolism, pathology)
• Protein Kinase Inhibitors (pharmacology)
• Up-Regulation (drug effects)