Document Detail


Mucronulatol from Caribbean propolis exerts cytotoxic effects on human tumor cell lines.
MedLine Citation:
PMID:  18538108     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVE: Mucronulatol is one of the most cytotoxic substances present in Caribbean propolis. This work aimed at initially characterizing the biological effects of mucronulatol in cancer cell lines comprehending both wildtype and resistant sublines. MATERIALS AND METHODS: An RP-HPLC technique was employed to separate and purify mucronulatol. IC(50) values were determined using the sulforhodamine B (SRB) proliferation assay. FACS-based cell cycle studies were carried out combining propidium iodide staining and 5-bromo-2'-deoxyuridine incorporation. Cell cycle regulator proteins were detected by Western blotting. The transcription of genes of interest was analyzed using RT-PCR. RESULTS: In MDR1-/MDR3+ cells, mucronulatol exhibited cytotoxicity in the range of 2.7 - 10.2 microg/ml, while no cytotoxic effects were observed in MDR1+ systems at up to 100 microg/ml. Cytometric studies revealed that mucronulatol promoted a global reduction in all cell cycle phases, with a remarkable increase of the apoptotic sub-G1 population. Immunoblotting showed that mucronulatol induced an up-regulation of p21(Cip1) and p27(Kip1) while down-regulating cyclin E and CDK4 in a drug concentration-dependent manner. No effect on topoisomerase I was observed, while we detected an altered expression of topoisomerases II-I+/-/I(2). RT-PCR studies showed that 2-fold the IC(50) in HCT8 colon carcinoma cells was sufficient for altering the expression pattern of genes in this cell line, including topoisomerase I, thymidilate synthase, EGF receptor and c-myc, amongst others. CONCLUSION: Here, we demonstrate for the first time that mucronulatol exerts cytotoxicity in cancer cell lines by targeting the control of cell cycle progression, indicating that the mechanism of action of this compound involves interference with the cell cycle machinery.
Authors:
D Diaz-Carballo; M Freistã Hler; S Malak; W Bardenheuer; H P Reusch
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  International journal of clinical pharmacology and therapeutics     Volume:  46     ISSN:  0946-1965     ISO Abbreviation:  Int J Clin Pharmacol Ther     Publication Date:  2008 May 
Date Detail:
Created Date:  2008-06-09     Completed Date:  2008-08-18     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9423309     Medline TA:  Int J Clin Pharmacol Ther     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  226-35     Citation Subset:  IM    
Affiliation:
Abteilung Klinische Pharmakologie, Ruhr-Universität Bochum, Germany. david.diaz-carballo@rub.de
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / chemistry,  isolation & purification*,  pharmacology*
Blotting, Western
Cell Cycle / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Chromatography, High Pressure Liquid
Drug Resistance, Neoplasm
Humans
Indigofera*
Isoflavones / chemistry,  isolation & purification*,  pharmacology*
Magnetic Resonance Spectroscopy
Mass Spectrometry
Reverse Transcriptase Polymerase Chain Reaction
West Indies
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Isoflavones; 0/mucronulatol

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