title: Cell permeable Bcl-2 binding peptides: a chemical approach to apoptosis induction in tumor cells.
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.
authors.affiliation: Kimmel Cancer Center, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Wang
authors.forename: Z J
authors.initials: ZJ
authors.lastname: Zhang
authors.forename: S
authors.initials: S
authors.lastname: Choksi
authors.forename: S
authors.initials: S
authors.lastname: Shan
authors.forename: Z
authors.initials: Z
authors.lastname: Lu
authors.forename: C M
authors.initials: CM
authors.lastname: Croce
authors.forename: E S
authors.initials: ES
authors.lastname: Alnemri
authors.forename: R
authors.initials: R
authors.lastname: Korngold
authors.forename: Z
authors.initials: Z
authors.lastname: Huang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002463:Cell Membrane Permeability; D002470:Cell Survival / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D018922:HL-60 Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008969:Molecular Sequence Data; D009374:Neoplasms, Experimental / Q000401:mortality / Q000473:pathology / Q000517:prevention & control; D009842:Oligopeptides / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D016019:Survival Analysis; D015996:Survival Rate; D051025:bcl-Associated Death Protein
chemical_list: C494819:BAD protein, human; C494820:Bad protein, mouse; D002352:Carrier Proteins; D009842:Oligopeptides; D019253:Proto-Oncogene Proteins c-bcl-2; D051025:bcl-Associated Death Protein