Document Detail

Autophagy-mediated chemosensitizing effect of the plant alkaloid voacamine on multidrug resistant cells.
MedLine Citation:
PMID:  17070665     Owner:  NLM     Status:  MEDLINE    
In our previous studies, voacamine, a bisindolic alkaloid extracted from Peschiera fuchsiaefolia, was examined for its possible capability of enhancing the cytotoxic effect of doxorubicin (DOX) on multidrug resistant (MDR) human osteosarcoma cells (U-2 OS-R). Voacamine induced in resistant cells a significant increase of drug retention and intranuclear location which became comparable to those observed in the parental sensitive counterparts (U-2 OS-WT). In the present study, the cell survival analysis and the electron microscopic observations confirmed the evident cytotoxicity of DOX on MDR cells after pre-treatment with the plant extract. Moreover, an increase of the reactivity of P-glycoprotein (P-gp) with the monoclonal antibody UIC2, which recognizes an epitope of the drug transporter in its functional conformation, was revealed, demonstrating that voacamine is a substrate of P-gp, thus acting as a competitive antagonist of the cytotoxic agent. Moreover, to investigate if the enhancement of the cytotoxic effect induced by voacamine could be due to an apoptotic process, we carried out the analysis of cell morphology after Hoechst staining and the quantification of apoptosis by Annexin V-FITC assay. These evaluations showed a very low rate of apoptosis in U-2 OS-R cells treated with voacamine and DOX given in association. In addition, the combined treatment induced ultrastructural modifications suggestive of autophagic cell death. In particular, transmission electron microscopy observations revealed the presence of numerous lysosomes and the formation of a large number of autophagosomes containing residual digested material. In conclusion, these findings seem to indicate that voacamine is capable of enhancing the cytotoxic effect of DOX on MDR cells by favouring a lethal autophagic process.
S Meschini; M Condello; M Marra; G Formisano; E Federici; G Arancia
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2006-09-16
Journal Detail:
Title:  Toxicology in vitro : an international journal published in association with BIBRA     Volume:  21     ISSN:  1879-3177     ISO Abbreviation:  Toxicol In Vitro     Publication Date:  2007 Mar 
Date Detail:
Created Date:  2007-02-12     Completed Date:  2009-07-21     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8712158     Medline TA:  Toxicol In Vitro     Country:  England    
Other Details:
Languages:  eng     Pagination:  197-203     Citation Subset:  IM    
Department of Technology and Health, Italian National Institute of Health, Rome, Italy.
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MeSH Terms
Apoptosis / drug effects
Cell Line, Tumor
Doxorubicin / pharmacology
Drug Resistance, Multiple
Drug Resistance, Neoplasm
Ibogaine / analogs & derivatives*,  pharmacology
Microscopy, Electron, Scanning
Osteosarcoma / drug therapy,  pathology
P-Glycoprotein / chemistry
Protein Conformation
Reg. No./Substance:
0/P-Glycoprotein; 23214-92-8/Doxorubicin; 3371-85-5/voacamine; 83-74-9/Ibogaine

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