Abstract
Bcl-2 is a potent suppressor of apoptosis, and its overexpression contributes to tumorigenesis in many types of human cancers. To test the possibility of modulating Bcl-2 function as an anticancer strategy, a cell permeable Bcl-2 binding peptide, cell permeable moiety (cpm)-1285, was designed by chemically attaching a fatty acid to a peptide derived from the proapoptotic protein Bad. cpm-1285 entered HL-60 tumor cells, bound Bcl-2 protein, and induced apoptosis in vitro. In contrast, cpm-1285 had little effect on normal human peripheral blood lymphocytes. Furthermore, cpm-1285 had in vivo activity in slowing human myeloid leukemia growth in severe combined immunodeficient mice. These results demonstrate a novel approach for therapeutic intervention of tumor growth in vivo with small molecule inhibitors of Bcl-2.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Apoptosis / drug effects
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Carrier Proteins / chemistry
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Carrier Proteins / metabolism
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Carrier Proteins / pharmacology
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Cell Membrane Permeability
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Cell Survival / drug effects
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DNA Fragmentation / drug effects
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Dose-Response Relationship, Drug
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HL-60 Cells / cytology
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HL-60 Cells / drug effects
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HL-60 Cells / metabolism
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Humans
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Mice
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Mice, Inbred C57BL
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Mice, SCID
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Molecular Sequence Data
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Neoplasms, Experimental / mortality
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Neoplasms, Experimental / pathology
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Neoplasms, Experimental / prevention & control
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Oligopeptides / chemical synthesis
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Oligopeptides / metabolism*
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Oligopeptides / pharmacology
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Protein Binding
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Proto-Oncogene Proteins c-bcl-2 / metabolism*
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Survival Analysis
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Survival Rate
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bcl-Associated Death Protein
Substances
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BAD protein, human
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Bad protein, mouse
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Carrier Proteins
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Oligopeptides
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Proto-Oncogene Proteins c-bcl-2
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bcl-Associated Death Protein