title: A novel microtubule de-stabilizing complementarity-determining region C36L1 peptide displays antitumor activity against melanoma in vitro and in vivo.
abstract: Short peptide sequences from complementarity-determining regions (CDRs) of different immunoglobulins may exert anti-infective, immunomodulatory and antitumor activities regardless of the specificity of the original monoclonal antibody (mAb). In this sense, they resemble early molecules of innate immunity. C36L1 was identified as a bioactive light-chain CDR1 peptide by screening 19 conserved CDR sequences targeting murine B16F10-Nex2 melanoma. The 17-amino acid peptide is readily taken up by melanoma cells and acts on microtubules causing depolymerization, stress of the endoplasmic reticulum and intrinsic apoptosis. At low concentrations, C36L1 inhibited migration, invasion and proliferation of B16F10-Nex2 cells with cell cycle arrest at G2/M phase, by regulating the PI3K/Akt signaling axis involving Rho-GTPase and PTEN mediation. Peritumor injection of the peptide delayed growth of subcutaneously grafted melanoma cells. Intraperitoneal administration of C36L1 induced a significant immune-response dependent anti-tumor protection in a syngeneic metastatic melanoma model. Dendritic cells stimulated ex-vivo by the peptide and transferred to animals challenged with tumor cells were equally effective. The C36 VL CDR1 peptide is a promising microtubule-interacting drug that induces tumor cell death by apoptosis and inhibits metastases of highly aggressive melanoma cells.
authors.affiliation: Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo (UNIFESP), São Paulo, São Paulo, Brazil.
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Figueiredo
authors.affiliation: Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo (UNIFESP), São Paulo, São Paulo, Brazil.
authors.forename: Alisson L
authors.initials: AL
authors.lastname: Matsuo
authors.affiliation: Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Ricardo A
authors.initials: RA
authors.lastname: Azevedo
authors.affiliation: Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo (UNIFESP), São Paulo, São Paulo, Brazil.
authors.forename: Mariana H
authors.initials: MH
authors.lastname: Massaoka
authors.affiliation: Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo (UNIFESP), São Paulo, São Paulo, Brazil.
authors.forename: Natalia
authors.initials: N
authors.lastname: Girola
authors.affiliation: Microbiology and Virology Unit, Department of Biomedical, Biotechnological and Translational Sciences, Universitá degli Studi di Parma, Parma, Italy.
authors.forename: Luciano
authors.initials: L
authors.lastname: Polonelli
authors.affiliation: Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo (UNIFESP), São Paulo, São Paulo, Brazil.|Recepta Biopharma, São Paulo, SP, Brazil.
authors.forename: Luiz R
authors.initials: LR
authors.lastname: Travassos
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D022801:Complementarity Determining Regions / Q000737:chemistry*; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D008546:Melanoma, Experimental; D051379:Mice; D008870:Microtubules / Q000737:chemistry / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009362:Neoplasm Metastasis; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D055503:Protein Multimerization / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D022801:Complementarity Determining Regions; D010455:Peptides; D014404:Tubulin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; D020741:rho GTP-Binding Proteins