Bovine lactoferricin induces caspase-independent apoptosis in human B-lymphoma cells and extends the survival of immune-deficient mice bearing B-lymphoma xenografts

• Published in: Experimental and molecular pathology Vol. 88; no. 3; pp. 371 - 375
• Main Authors: Furlong, Suzanne J., Mader, Jamie S., Hoskin, David W.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01.06.2010; Elsevier
• Subjects: Amino Acid Sequence; Animals; Antimicrobial Cationic Peptides - chemistry; Antimicrobial Cationic Peptides - pharmacology; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; B-cell lymphoma; Biological and medical sciences; Bovine lactoferricin; Caspase 3 - metabolism; Cattle; Cell Line, Tumor; Culture Media; Hematologic and hematopoietic diseases; Humans; Investigative techniques, diagnostic techniques (general aspects); Lactoferrin - chemistry; Lactoferrin - pharmacology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphoma, B-Cell - drug therapy; Lymphoma, B-Cell - enzymology; Lymphoma, B-Cell - pathology; Medical sciences; Mice; Mice, SCID; Molecular Sequence Data; Neoplasm Transplantation; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Serum Albumin, Bovine; Transplantation, Heterologous; Bovine lactoferricin; B-cell lymphoma; Apoptosis; Cysteine endopeptidases; Heterograft; Heterotransplantation; Lymphoproliferative syndrome; β Cell; Ungulata; Tumor cell; Human; Cell survival; Bovine; Enzyme; Deficiency; Rodentia; Caspase; B cell neoplasm; Malignant hemopathy; B-Lymphocyte; Lymphoma; Peptidases; Vertebrata; Anatomic pathology; Mammalia; Mouse; Cell death; Animal; Hydrolases; Artiodactyla; Cancer
• ISSN: 0014-4800; 1096-0945
• DOI: 10.1016/j.yexmp.2010.02.001

Although current treatments based on the use of B-cell-specific anti-CD20 monoclonal antibodies and aggressive combinatorial chemotherapy have improved the survival of patients suffering from B-cell non-Hodgkin's lymphoma (NHL), some individuals fail to respond to treatment and relapses remain common. New and more effective treatments for B-cell NHL are therefore required. Bovine lactoferricin (LfcinB) is a cationic antimicrobial peptide that is cytotoxic for several human tumor cell lines but does not harm healthy cells. Here we show that in vitro treatment with LfcinB caused Raji and Ramos human B-lymphoma cells to die by apoptosis, as indicated by DNA fragmentation, chromatin condensation, and nuclear disintegration. LfcinB killed B-lymphoma cells more efficiently at low serum concentrations and was inhibited in the presence of exogenous bovine serum albumin, suggesting partial neutralization of cationic LfcinB by anionic serum components. LfcinB-induced apoptosis in B-lymphoma cells was caspase-independent since caspase-3 activation was not detected by Western blotting and the general caspase inhibitor z-VAD-fmk did not prevent LfcinB-induced DNA fragmentation. Importantly, immune-deficient SCID/beige mice that were inoculated intravenously with Ramos B-lymphoma cells in order to model B-cell NHL exhibited extended survival following systemic administration of LfcinB, indicating that LfcinB warrants further investigation as a novel therapeutic agent for the possible treatment of B-cell NHL.