title: Recombinant lysyl oxidase propeptide protein inhibits growth and promotes apoptosis of pre-existing murine breast cancer xenografts.
abstract: Lysyl oxidase propeptide (LOX-PP) ectopic overexpression inhibits the growth of cancer xenografts. Here the ability and mode of action of purified recombinant LOX-PP (rLOX-PP) protein to inhibit the growth of pre-existing xenografts was determined. Experimental approaches employed were direct intratumoral injection (i.t.) of rLOX-PP protein into murine breast cancer NF639 xenografts, and application of a slow release formulation of rLOX-PP implanted adjacent to tumors in NCR nu/nu mice (n = 10). Tumors were monitored for growth, and after sacrifice were subjected to immunohistochemical and Western blot analyses for several markers of proliferation, apoptosis, and for rLOX-PP itself. Direct i.t. injection of rLOX-PP significantly reduced tumor volume on days 20, 22 and 25 and tumor weight at harvest on day 25 by 30% compared to control. Implantation of beads preloaded with 35 micrograms rLOX-PP (n = 10) in vivo reduced tumor volume and weight at sacrifice when compared to empty beads (p<0.05). A 30% reduction of tumor volume on days 22 and 25 (p<0.05) and final tumor weight on day 25 (p<0.05) were observed with a reduced tumor growth rate of 60% after implantation. rLOX-PP significantly reduced the expression of proliferation markers and Erk1/2 MAP kinase activation, while prominent increases in apoptosis markers were observed. rLOX-PP was detected by immunohistochemistry in harvested rLOX-PP tumors, but not in controls. Data provide pre-clinical findings that support proof of principle for the therapeutic anti-cancer potential of rLOX-PP protein formulations.
authors.affiliation: Division of Oral Biology, Boston University Henry M. Goldman School of Dental Medicine, Boston, Massachusetts, United States of America.
authors.forename: Manish V
authors.initials: MV
authors.lastname: Bais
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Nugent
authors.forename: Danielle N
authors.initials: DN
authors.lastname: Stephens
authors.forename: S Selva
authors.initials: SS
authors.lastname: Sume
authors.forename: Kathrin H
authors.initials: KH
authors.lastname: Kirsch
authors.forename: Gail E
authors.initials: GE
authors.lastname: Sonenshein
authors.forename: Philip C
authors.initials: PC
authors.lastname: Trackman
mesh_terms: D000464:Alginates; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003692:Delayed-Action Preparations; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D020287:In Situ Nick-End Labeling; D019394:Ki-67 Antigen / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D008863:Microspheres; D010455:Peptides / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D008249:Protein-Lysine 6-Oxidase / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000464:Alginates; D014408:Biomarkers, Tumor; D003692:Delayed-Action Preparations; D006657:Histones; D019394:Ki-67 Antigen; D010455:Peptides; D011994:Recombinant Proteins; D008249:Protein-Lysine 6-Oxidase; D048049:Extracellular Signal-Regulated MAP Kinases; D053148:Caspase 3