| pH-(low)-insertion-peptide (pHLIP) translocation of membrane impermeable phalloidin toxin inhibits cancer cell proliferation. | |
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MedLine Citation:
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PMID: 21048084 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Ming An; Dayanjali Wijesinghe; Oleg A Andreev; Yana K Reshetnyak; Donald M Engelman |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-11-03 |
Journal Detail:
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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:
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Created Date: 2010-11-24 Completed Date: 2011-01-20 Revised Date: 2011-07-28 |
Medline Journal Info:
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Nlm Unique ID: 7505876 Medline TA: Proc Natl Acad Sci U S A Country: United States |
Other Details:
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Languages: eng Pagination: 20246-50 Citation Subset: IM |
Affiliation:
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Department of Molecular Biophysics and Biochemistry, Yale University, P.O. Box 208114, New Haven, CT 06520, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Actins
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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:
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CA133890/CA/NCI NIH HHS; GM073857/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Actins; 0/Membrane Proteins; 0/Mycotoxins; 0/Phosphatidylcholines; 0/pHLIP protein; 17466-45-4/Phalloidine; 6753-55-5/1-palmitoyl-2-oleoylphosphatidylcholine |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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