Document Detail


pH-(low)-insertion-peptide (pHLIP) translocation of membrane impermeable phalloidin toxin inhibits cancer cell proliferation.
MedLine Citation:
PMID:  21048084     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
We find that pH-(low)-insertion-peptide (pHLIP)-facilitated translocation of phalloidin, a cell-impermeable polar toxin, inhibits the proliferation of cancer cells in a pH-dependent fashion. The monomeric pHLIP inserts its C terminus across a membrane under slightly acidic conditions (pH 6-6.5), forming a transmembrane helix. The delivery construct carries phalloidin linked to its inserting C terminus via a disulfide bond that is cleaved inside cells, releasing the toxin. To facilitate delivery of the polar agent, a lipophilic rhodamine moiety is also attached to the inserting end of pHLIP. After a 3 h incubation at pH 6.1-6.2 with 2-4 μM concentrations of the construct, proliferation in cultures of HeLa, JC, and M4A4 cancer cells is severely disrupted (> 90% inhibition of cell growth). Treated cells also show signs of cytoskeletal immobilization and multinucleation, consistent with the expected binding of phalloidin to F actin, stabilizing the filaments against depolymerization. The antiproliferative effect was not observed without the hydrophobic facilitator (rhodamine). The biologically active delivery construct inserts into 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine lipid bilayers with an apparent pK(a) of ∼6.15, similar to that of the parent pHLIP peptide. Sedimentation velocity experiments show that the delivery construct is predominantly monomeric (> 90%) in solution under the conditions employed to treat cells (pH 6.2, 4 μM). These results provide a lead for antitumor agents that would selectively destroy cells in acidic tumors. Such a targeted approach may reduce both the doses needed for cancer chemotherapy and the side effects in tissues with a normal pH.
Authors:
Ming An; Dayanjali Wijesinghe; Oleg A Andreev; Yana K Reshetnyak; Donald M Engelman
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-11-03
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  107     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2010 Nov 
Date Detail:
Created Date:  2010-11-24     Completed Date:  2011-01-20     Revised Date:  2014-04-16    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  20246-50     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Actins / metabolism
Amanita / chemistry*
Cell Line, Tumor
Cell Proliferation / drug effects*
Humans
Hydrogen-Ion Concentration
Membrane Proteins / metabolism*
Molecular Structure
Mycotoxins / metabolism,  pharmacology*
Neoplasms / drug therapy*
Phalloidine / metabolism,  pharmacology*
Phosphatidylcholines / metabolism
Protein Transport / physiology
Grant Support
ID/Acronym/Agency:
CA133890/CA/NCI NIH HHS; GM073857/GM/NIGMS NIH HHS; R01 CA133890/CA/NCI NIH HHS; R01 GM073857/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Actins; 0/Membrane Proteins; 0/Mycotoxins; 0/Phosphatidylcholines; 0/pHLIP protein; 17466-45-4/Phalloidine; TE895536Y5/1-palmitoyl-2-oleoylphosphatidylcholine
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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