title: Targeted delivery of a phosphopeptide prodrug inhibits the proliferation of a human glioma cell line.
abstract: Peptides are ideal candidates for developing therapeutics. Polo-like kinase 1 is an important regulatory protein in the cell cycle and contains a C-terminal polo-box domain, which is the hallmark of this protein family. We developed a peptide inhibitor of polo-like kinase 1 that targets its polo-box domain. This new phosphopeptide, cRGDyK-S-S-CPLHSpT, preferentially penetrates the cancer cell membrane mediated by the integrin receptor, which is expressed at high levels by cancer cells. In the present study, using high performance liquid chromatography and mass spectroscopy, we determined the stability of cRGDyK-S-S-CPLHSpT and its cleavage by glutathione under typical conditions for cell culture. We further assessed the ability of the peptide to inhibit the proliferation of the U87MG glioma cell line. The phosphorylated peptide was stable, and the disulfide bond of cRGDyK-S-S-CPLHSpT was cleaved in 50 mM glutathione. This peptide inhibited the growth of cancer cells and changed their morphology. Therefore, we conclude that the phosphopeptide shows promise as a prodrug and has a high potential to act as an anticancer agent by inhibiting polo-like kinase 1 by binding its polo-box domain. These findings indicate the therapeutic potential of PLHSpT and peptides similarly targeted to surface receptors of cancer cells and to the functional domains of regulatory proteins.
authors.affiliation: Division of Magnetic Resonance Research, Korea Basic Science Institute (KBSI), Chungbuk, Republic of Korea.
authors.forename: Sung-min
authors.initials: SM
authors.lastname: Kim
authors.forename: Sun Mi
authors.initials: SM
authors.lastname: Yoon
authors.forename: Min Su
authors.initials: MS
authors.lastname: Yim
authors.forename: Gyunggoo
authors.initials: G
authors.lastname: Cho
authors.forename: Eun Kyoung
authors.initials: EK
authors.lastname: Ryu
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005910:Glioma / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D015394:Molecular Structure; D010748:Phosphopeptides / Q000737:chemistry / Q000494:pharmacology*; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D010748:Phosphopeptides; D011355:Prodrugs; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1