Document Detail


Paclitaxel-hyaluronan hydrosoluble bioconjugate: Mechanism of action in human bladder cancer cell lines.
MedLine Citation:
PMID:  22341413     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
OBJECTIVES: A previously described hydrosoluble paclitaxel-hyaluronan bioconjugate appears particularly well suited for treatment of superficial bladder cancer because of its in vitro cytotoxic profile against urothelial carcinoma (UC) cell lines and in vivo biocompatibility. The aim of this work was to assess the mechanism of action of the bioconjugate in UC cells. MATERIALS AND METHODS: Expression of CD44 and RHAMM hyaluronan-binding receptors in RT-4 and RT-112/84 UC cell lines, interaction of fluorochrome-labeled bioconjugate with tumor cells, CD44 modulation upon incubation with the compound or free hyaluronan, and caspase activation were assessed by flow cytometry. Cytotoxicity was studied by the MTT assay. Analysis of bioconjugate intracellular localization and effects on β-tubulin organization was carried out by confocal microscopy. RESULTS: The paclitaxel-hyaluronan bioconjugate bound to UC tumor cells entered intracellular compartments through a saturable and energy-dependent mechanism that involved CD44, as assessed by blocking with specific antibody. Upon internalization, the bioconjugate accumulated into lysosomes where the esteric bond between paclitaxel and the hyaluronan moiety was cleaved, leading to cytoplasmic diffusion of the free drug, caspase activation, and disruption of the β-tubulin microtubular mesh with subsequent cell death. CONCLUSIONS: Conjugation of paclitaxel to hyaluronan results in a new chemical entity, characterized by selective targeting to polymer receptors on plasma membrane and cell entry through receptor-mediated endocytosis, followed by lysosomal accumulation. Ultimately, the active molecule is released, fully preserving the cytotoxic potential and profile of clinically used free paclitaxel.
Authors:
Isabella Monia Montagner; Alessandra Banzato; Gaia Zuccolotto; Davide Renier; Monica Campisi; Pierfrancesco Bassi; Paola Zanovello; Antonio Rosato
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-2-16
Journal Detail:
Title:  Urologic oncology     Volume:  -     ISSN:  1873-2496     ISO Abbreviation:  -     Publication Date:  2012 Feb 
Date Detail:
Created Date:  2012-2-20     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9805460     Medline TA:  Urol Oncol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012 Elsevier Inc. All rights reserved.
Affiliation:
Istituto Oncologico Veneto IRCCS, Padova, Italy.
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